Research Report of the Medical Faculty 2015
Reference Period 2013 - 2014
General Aspects
Content
General Aspects______3
Preclinical Institutions Institute of Anatomy and Cell Biology______12 Institute of Molecular Biology and Tumorbiology (IMT)______17 Institute of Physiological Chemistry______23 Institute of Physiology and Pathophysiology______25 Department of Medical Psychology______31 Institute of Medical Sociology and Social Medicine______34
Clinical-theoretical Institution Institute of General and Family Medicine, Prevention and Rehabilitations______36 Institute of Medical Biometry and Epidemiology______39 Institute of Pharmacology and Toxicology______41 Emil-von-Behring-Library, Department of the History of Medicine______44 Institute of Clinical Cytobiology and Cytopathology______46 Institute of Immunology______49 Institute of Medical Microbiology and Hospital Hygiene______51 Institute of Virology______54 Centre for Human Genetics______61 Institute of Pathology______62 Division of Neuropathology______64 Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics______66 Institute for Lung Research ______69
Clinical Institutions Department of Anaesthesia and Intensive Care Therapy______73 Department of Diagnostic and Interventional Radiology______75 Department of Nuclear Medicine______78 Department of Radiotherapy and Radiooncology______81 Department of Internal Medicine: Division of Gastroenterology, Endocrinology and Metabolism______84 Department of Internal Medicine: Division of Hematology, Oncology and Immunology______89 Department of Internal Medicine: Division of Cardiology______95 Department of Internal Medicine: Division of Pneumology______97 Department of Internal Medicine: Division of Psychosomatic Medicine and Psychotherapy______101 Department of Cardiovascular Surgery______103 Department of Neurosurgery______105 Department of Orthopaedics and Rheumatology______107 Department of Trauma, Hand- and Reconstructive Surgery______110 Department of Urology and Pediatric Urology – Prostate Cancer Centre______112 Department of Visceral-, Thoracic and Vascular Surgery______113 Department of Gynaecology, Gynaecological Endocrinology and Oncology______115 Children’s Hospital______118 Department of Otolaryngology, Head and Neck Surgery______120 Department of Ophthalmology______123 Departement of Dermatology and Allergology______125 Department of Neurology______130 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy ______136 Department of Psychiatry and Psychotherapy______140 Department of Oral and Maxillofacial Surgery, Oral Surgery and Implantology______147 Department of Orthodontics______151 Departement of Periodontology______152 Department of Operative Density and Endodontics______154 Department of Pediatric and Community Density______156 Department of Prosthodontics and Craniomandibular Function______158 Coordination Centre for Clinical Trials______162 List of Abbreviations/Glossary
BMBF Federal Ministry of Education and Research – Bundesministerium für Bildung und Forschung
BMFZ Biomedical Research Centre – Biomedizinisches Forschungszentrum
CCC Comprehensive Cancer Center
DFG German Research Foundation / Deutsche Forschungsgemeinschaft
FOR Research Unit / Forschergruppe
GRK Research Training Group / Graduiertenkolleg
IMT Institute for Molecular Biology and Tumor Research
JIF Journal Impact Factor
KFO Clinical Research Unit / Klinische Forschergruppe
KKS Coordination Centre for Clinical Studies
LOEWE State Offensive for the Development of Scientific-Economic Excellence / Landes-Offensive zur Entwicklung
Wissenschaftlich-ökonomischer Exzellenz
LOF Performance-related allocation of research and office space
LOM Performance-related Funding / Leistungsorientierte Mittelvergabe
SFB Collaborative Research Centre / Sonderforschungsbereich
SFB/TR TR Transregional Collaborate Research Centre / Transregio
UKGM University Hospital Giessen and Marburg Universitätsklinikum Gießen
und Marburg
ZTI Centre for Tumor and Immunobiology/ Zentrum für Tumor- und Immunbiologie
General Aspects General Aspects technology including proteomics, genomics, live-cell and super-resolution imaging methods. The groups Main Fields of Research also exploit pathologically altered cells to analyze According to the criteria of the German Research and compare the changes in the intracellular Council (DFG) at the School of Medicine of the compartments in order to define and distinguish Philipps University Marburg the following preferred normal and pathologically altered processes at the research clusters are established: molecular level. A unifying goal of the research groups in this area is the identification and characterization of the molecular machineries Cellular Compartimentation and Disease participating in the biogenesis, maintenance and Relevance dynamic alteration of the various compartments of a Clinical Immunology and Infection Biology eukaryotic cell. Further, the groups try to unravel the Oncology and Tumor Biology mechanisms underlying the intracellular transport of Neuroscience proteins, nucleic acids, lipids, metabolites, and
metals. Associated infrastructural components already Another central focus is on the impact of (highly existent are the Biomedical Research Centre (BMFZ), pathogenic) viruses, intracellular parasites, and the Institute for Molecular Biology and Tumor fungal pathogens on intracellular Research (IMT), the Center for Tumorbiology and compartmentalization, and on the importance of Immunology (ZTI) the Comprehensive Cancer Center compartment-specific tropism for pathogen Marburg (CCC), the Carreras Leukaemia Centre and reproduction and host cell toxicity. The common the Allergy Centre Hesse. goal of these projects is the elucidation of how these
pathogens alter and exploit cellular compartments
to ensure their own survival. The thorough Research Cluster „Cellular Compartmentation mechanistic investigation of the molecular basis of and its Relevance for Disease“ intracellular compartmentation is a prerequisite for The location of intracellular compartments and the understanding of the disease-relevant smaller entities such as protein complexes, nucleic phenotypes and the long-term development of acids, metals and lipids within a cell is prerequisite therapeutic regimes. for the complexity and regulation of the biological functions performed by this particular cell. Failure to The research cluster has been funded by several accurately localize cellular biomolecules is frequently coordinated programs of DFG. This includes a associated with disease. In order to generate, Collaborative Research Center (SFB 593), a Graduate maintain and modulate biogenesis, composition and Research Training Group (GRK 1216), and a Research location of various intracellular compartments, Unit (FOR 1086). All these coordinate funding eukaryotic cells have developed sophisticated programs have terminated in 2015. Efforts are machineries to ensure transport of metals, currently on the way to acquire new funding metabolites, lipids, proteins, and nucleic acids across opportunities within coordinated programs. These membranes and to support membrane trafficking efforts are undertaken with partners from the within the cell. Work in the Research Cluster University of Giessen. „Cellular Compartmentation and its Relevance for Disease“ (Figure) is dedicated to the elucidation of We entertain intensive contacts with the Research the molecular mechanisms underlying various Clusters of Tumor Biology and Immune and membrane transport and compartmentalization Infection Biology, since it has become evident that processes in eukaryotic cells using yeast, pathogenic the problem of correct (sub-)cellular location also fungi, human cell culture, and mice as model applies to these areas (Figure). Vice versa, the systems. Participating groups of Philipps University regulatory and signaling mechanisms studied within and the Max-Planck-Institute for Terrestric these two Clusters are of increasing interest for our Microbiology analyze the mechanistic basis of the area in order to understand how the cell maintains generation and maintenance of the intracellular its overall homeostasis. As a consequence of these compartmentation by using state-of-the-art mutual interests in the two clusters, the participating research groups jointly address the regulation of the
Research Report of the Medical Faculty of the Philipps University Marburg - Reference period 2013-2014 3
General Aspects intracellular localization of proteins, RNA and lipids Study of transport processes between host cells in healthy cells and after tumorigenic and infectious and the malaria pathogen Plasmodium alterations. The signaling pathways leading to falciparum and its relevance for the lifecycle of alterations in cellular compartmentation in response the pathogen to changing physiological conditions or external Investigation of the changes in intracellular challenges are also studied jointly. compartmentation during the plant cell infection by pathogenic fungi Our Research Cluster maintains fruitful contacts to Analysis of mechanisms how highly pathogenic and collaborations with the faculties of Biology, viruses (Influenza, Marburg, Ebola, Lassa, Dengue Chemistry and Pharmacy, as well as the Max-Planck- etc.) exploit and alter the intracellular compart- Institute of Terrestrial Microbiology (Figure). Finally, ments (mainly the nucleus and secretory we participate in the activities of the LOEWE Center apparatus) for the own proliferation of Synthetic Microbiology.
Diseases include Examples for research projects in this area: Disorders of transport processes with relevance Analysis of the mechanisms of the intracellular for tumor development vesicle transport and the molecular basis of cell Ion channel diseases polarization of, e.g., polarized epithelial cells Sugar transport diseases Investigation of the role of mitochondria, cytosol Neurological disorders associated with the and nucleus in the biogenesis of iron-sulfur erroneous trafficking of macromolecules involved proteins and the relevance for in intracellular transport neurodegenerative, metabolic, and Hypertension hematological diseases Various iron storage diseases, myopathies and Analysis of the mechanisms of the intracellular anemias, and diverse neurological diseases transport, subcellular localization, membrane (Lowe-, Bartter- und Anderson-Syndrome, microcompartmentation of ion channels and Friedreich Ataxia) with a primary defect in the lipids in the activation of signal-transducing intracellular compartmentation processes (e.g., in caveolae) Mitochondrial fatal encephalopathies and Investigation of various aspects of nucleo-cyto- myopathies with multiple metabolic disorders plasmic transport and protein und (micro)RNA Plant infections by pathogenic fungi (smut) transport across biological membranes Various viral diseases such as influenza and hemorrhagic fever
Fig. 1: Structure of the research cluster “Cellular Compartmentation and its Relevance for Disease” and its integration into the Marburg research landscape. Activities in red have been terminated in 2015
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Research Cluster “Clinical Immunology and (DZL) UGMLC is one of six national research centres Infection Biology” for health. DZL has already taken up his research activities end of 2011. A main focus of the Marburg The research focus area “Clinical Immunology and group within the DZL is the chronic inflammatory Infection Biology” is mainly concerned on the one lung illnesses asthma and COPD. hand with the immunopathogenesis of chronic inflammatory processes, among which rate Marburg University has a long tradition in working autoimmune diseases and allergies on the other with highly pathogenic viruses which goes back to hand with the pathogenesis of viruses that cause the isolation and characterization of Marburg virus in severe disease. 1967. Since then the focus of the Institute of Starting point to investigate chronic inflammatory Virology is to understand the biology and diseases was the awareness of a strong increase of pathogenesis of agents like Ebola, Lassa, Nipah and these disease entities, particularly since the end of influenza virus. The construction of facilities allowing the Second World War and most of all in the to work safely with these viruses was of crucial industrialised regions of the world. The phenomenal importance. Since 2008 the Philipps-University increase in these illnesses cannot be explained solely operates a modern Biosafety level 4 (BSL-4) by a genetic predisposition for the manifestation of laboratory where highly pathogenic viruses can be the phenotype (gene-gene-interactions). The investigated, without harming the scientists and the identification of protective or disease-promoting environment. Most of the highly pathogenic viruses environmental influences from life style and diet are zoonotic and transmission from the animal host have led to the so-called hygiene hypothesis, in to humans causes severe illness. Understanding the whose further development there was crucial impact viral and host factors that contribute to the severity by research groups from Marburg. In the of the disease course is important for developing Transregional Collaborate Research Centre SFB/TR novel antiviral strategies and effective vaccines. 22 ‘Allergic immune responses of the lung’ (Speaker These investigations are funded by the collaborative Prof. Renz) epidemiological evidence from research center SFB 593 (Speaker Prof. Lill, international prospective cohorts provides the basis http://www.uni-marburg.de/sfb593) and SFB 1021 for generating hypothesis. On the one hand the (Speaker Prof. Becker, http://www.uni- focus is on immunological regulation processes and marburg.de/sfb1021), the German Center for signal paths of the innate and acquired immune Infection Research (http://www.dzif.de/) as well as system. On the other hand failing signalling paths of many grants from the European Union. The resident cells of the lungs and the respiratory collaborative nature of these investigations becomes passages such as epithelia, fibroblasts and smooth obvious by the fact that within the funded networks muscle cells are investigated. Overall the consortium infection disease specialists work closely together follows a translational research approach aiming to with immunologists, cell biologists, clinical chemists, develop new concepts for prevention and to identify pharmaceutical chemists and biochemists from the new therapeutic targets, which will be clinically faculty of medicine at the Philipps-University and evaluated later in the project. This research field is other departments of the university. broadly established in the School of Medicine involving the Departments of Pneumology,
Dermatology and Pediatrics as well as the Institutes of Immunology, Medical Microbiology and Clinical
Chemistry. In 2009 the LOEWE-Centre UGMLC –
Universities Giessen and Marburg Lung Centre – was granted in collaboration with the Max-Planck-
Institute for Heart and Lung Research at Bad
Nauheim, in which the joint activities to explore infectious, inflammatory-allergic and vascular pulmonary diseases were brought together. In the recently established German centre for lung illnesses
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General Aspects
Fig. 2 “Organisation of the research cluster “Clinical Immonology and Infection Biology”
Research Cluster “Oncology and Tumor research building ‘Center for Tumor and Immune Biology” Biology’ that is funded by the BMBF and the State of Hessen. In the research focus “Oncology and Tumor Biology” one of the main questions is, how oncogenic Apart from this basic and translational research signaling, genetics and epigenetics interact to focus, the area of clinical oncology was continually generate a cancer phenotype characterized by and successfully developed. The central deregulation of proliferation control, invasive and organizational platform of clinical oncology is the metastatic growth, reprogramming of energy Anneliese Pohl Krebszentrum Marburg, metabolism, and drug resistance. Current funding Comprehensive Cancer Center (CCC). A new building programmes are the Transregional Collaborative for patient care and patient-oriented clinical Research Centre SFB/TRR17 ‘Ras-dependent research was erected by means of the Carreras pathways in human cancer’ (Speakers: Prof. Eilers, Leukemia Foundation (Carreras Leukämie Centrum, Würzburg and Prof. A. Neubauer, Marburg) and the Speaker Prof. A. Neubauer). The Carreras Leukämie Clinical Research Unit KFO 210 ‘Genetics of drug Centrum contains a ‘Clinical Trial Unit’, in which resistance in cancer’ (Speaker: Prof. A. Neubauer; experimental phase I/II studies concerning new Head: Prof. A.Burchert) as well as the Transregional signal modulators are carried out in cooperation Collaborative Research Centre SFB/TRR81 with the Marburg Coordination Centre for Clinical ‘Chromatin changes in differentiation and Studies (KKS). malignancies’ (Speaker: Prof. Brehm, Marburg). In this research center, dynamic alterations of the In addition, several accreditations have again been chromatin structure (epigenetics) in development successfully implemented in 2013-2014, for instance and cancer are at the forefront of research. a new “Onkologisches Zentrum” of the Deutsche Interactions between tumor cells and host cells in Krebsgesellschaft, that hosts several organ specific the microenvironment of the tumor, which tumor centers (oncomap.de). In Nov 2014, the significantly affect tumor growth and progression, international stem cell and leukemia accreditation are the focus of the LOEWE research cluster ‘Tumor JACIE was successfully implemented. & Inflammation’ (Speaker: Prof. Müller). Research on tumor-host interactions will be fueled by the new
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These accreditations underscore one important each for radiation biology and radiation physics will focus on clinical oncology at the university hospital be established. Additional translational projects in Marburg. In keeping with this, oncology will be the major research area tumor biology are supplemented in research and clinic by a Particle concerned e.g. with the pancreatic carcinoma the Therapy Centre. For research tasks a professorship EU-FP7 network “EPC-TM-NET”, “CAM-PaC”, BioPaC (all coordinated by Prof. T. Gress) and the national paramount interest and will serve as a basis for the case data base ‘Hereditary Pancreatic Carcinoma’ development of new molecular target-oriented, (‘FaPaCa’, Coordinator: Prof. D. Bartsch) the diagnostic and therapeutic methods. investigation of the molecular and genetic mechanisms of cancerogenesis in the pancreas of
Fig. 3 Structure of the research cluster “Oncology and Tumorbiology”
Research Cluster “Neuro Science” giessen.de/sfb) deals with basic mechanism of The scientific foci of the research cluster “Psycho- human sensory perception and is complementary to Neurosciences” are the aetiology of psychiatric and the IRTG1091 “The brain in action” (Speaker: Prof. neurological disorders as well as the improvement of Bremmer, http://www.irtg-brainact.de). Genetic and therapeutic interventions. epigenetic risk factors of neuro-psychiatric diseases There is a sharp increase in mental and neurological are being investigated in the EU-projects “MicroRNA disorders worldwide within the last decades. Mental function in homeostatic plasticity in the mammalian disorders are currently the most cost intensive non- brain” (EU, ERC-Grant “NEUROMIR”; coordinator: infectious diseases worldwide. Thus there is a Prof. Schratt) and MicroRNAs in epilepsy (EpimiRNA; pressing need to improve our etiological knowledge coordinator: Prof. Rosenow). More clinically and therapeutic interventions. These topics are focussed are the BMBF funded consortia “ASDnet” being investigated in several research consortia. The (Speaker: Prof. Kamp-Becker), “PROTECT-AD” FOR 2107 “Neurobiology of Affective Disorders” (anxiety disorders, sub-project coordinators: Profs. (Speaker: Prof. Kircher, www.FOR2107.de) focuses Straube/Kircher), “BipoLife” (bipolar disorder, sub- on gene x environment interactions on brain project coordinators Profs. Jansen/Kircher), and development and the neurobiological course of “ESCAlife” (ADHD, sub-project coordinator: Prof. illness in humans and rodent models. The SFB/TRR Becker) were genetic and environmental causes on 135 “Cardinal mechanisms of perception” (Speaker: outbreak and course of illness, early detection and Prof. Gegenfurtner, http://www.allpsych.uni- psychotherapeutic as well as neurobiological
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General Aspects therapies are being investigated. A Hertie Senior and IT is used for human research and a 7.0 T for Research Professorship has been awarded to Prof. animal MRI. Oertel so that he continues to work on Theses neuroscience activities at the University are neurodegerative diseases. being coordinated in the forthcoming "Centre for Important infrastructural facilities are the rodent Neuroscience". There are two newly established animal housings in the ZTI, the Biochemical- interdisciplinary master courses "Cognitive and Pharmacological Centre, the animal behaviour Integrative Systems Neurosciences (MSc)" and laboratory in the Faculty of Psychology, and the "Molecular and Cellular Neuroscience (MSc)". All primate facility. Two MR scanners have been co- neuroscience teaching is supported by the Graduate funded by the DFG and the University (DFG INST Center for Life and Natural Sciences in its Section 160/456-1). A 3 Tesla MRI scanner with personnel Experimental, Clinical and Cognitive Neuroscience (MARA).
Fig. 4 Structure of the Research Cluster Psycho-Neurosciences
Coordination Centre for Clinical Studies (KKS)
Since the establishment of coordinating centres for research (trial planning, conducting and evaluation clinical trials (KKS) by BMBF there is one of these including publication of the trial results) KKS centres at the department of medicine in Marburg. Marburg has taken over the following functions: KKS Marburg started in 2000. Focus of the work of Operating as sponsor for all investigator initiated KKS is to increase the quality of clinical trials and the trials with the principal investigator in Marburg acceptance of clinical research in the academic Handling of all contracts dealing with patient environment and to implement the principles of oriented research at the Philipps University "Good Clinical Practice" in everyday clinical practice. Marburg. In 2005, all funded KKS in germany have formed a Chair of the KKS network consortium (KKS Network). The network offers a Chair of the Networkworking group ‘data wide range of scientific services on a regional and management’ of the KKS Network national basis to scientists in universities, hospitals Chair of the Networkworking group ‘Monitoring’ and industry. Beyond the actual tasks in clinical of the KKS Network
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Deputy Chair of the Networkworking group ‘IT- The majority of supported clinical trails are systems’ of the KKS Network investigator initiated trials. These trials are partly Member of the European consortium ECRIN funded by the BMBF/DFG programm ‘Clinical trials’. (European Clinical Research Infrastructures KKS supports the investigators at the submission / Network and Biotherapy) call for proposals, conduct the trials and publishs Deputy chair of the working group ‘management the results in cooperation with the investigators. of clinical trials’ ot the TMF e.V. (Technologie und Methodenplattform für die vernetzte medizinische Forschung)
Coordinating Centre for Clinical Trials (KKS Marburg)
Quality Contract Planning and Conduct Education Moduls Management Management of Clinical Trials
Acting as Principal Contract design Biometrics Genomics Sponsor for CTs Investigator
Health SOP-System Contract review Data Management Investigator and IT Systems Economics
Auditing Preparation of Study Nurse contracts in Study Management Lung (UGMLC) multi-centre CTs and Monitoring
Pharmacovigilance
Fig. 5 Organisation chart of KKS Marburg
Technology-Transfer by TransMIT which aims to use transcription factors as innovative The translational research approach, particularly of targets for the treatment of chronic inflammations the clinically oriented research focus areas, leads to through the application of modern DNAzym- the generation of new knowledge and new technology (2nd place in the nationwide start-up technologies, whose innovative character has been competition „Science4Life“ 2007). recognised and whose intellectual authorship needs to be protected. For this purpose the TransMIT Society for Technology Transfer serves as the Research Funding potential transfer facility for the middle Hessian An overview of total research funding of the School universities and universities for applied science. of Medicine from 2004 to 2014 is given in Table 1 TransMIT was awarded the first rank in the and Fig. 6. This illustrates that the school has aquired evaluation of all university-based transfer institutes considerable funding by being awarded three in Germany (see also www.TransMIT.de). A number Collaborative Research Centres by the German of university professors and lecturers from Marburg Research Council. Overall third-party funding of the are involved in the TransMIT GmbH via TransMIT school in the last years amounts to around one third centres. The TransMIT GmbH is associated with the of the received state funding. During the last two Hessian Intellectual Property Offensive (HIPO) years this percentage has considerably increased. alliance. Arising from this transfer of innovation the company ’sterna biologicals’ has been founded,
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General Aspects
Performance-Related Internal Funding There is no direct ex-post parameter-controlled and The amount of funding of an institute received in the performance-related funding among the Medical annual LOM corresponds to its overall contribution Schools in the federal state of Hesse. in terms of publication performance and acquired Performance-related funding has been introduced at funding in relation to all other evaluated institutes. the School of Medicine at Marburg University fol- Currently the different sizes of institutes are not lowing the recommendations of the German considered in the assessment and do not enter into Research Council (DFG) from July 2004 on the calculation. ‚Performance- Related Funding’ (LOM) at Medical From the year 2010 the school aims to introduce Schools. Thereby the same rules apply for all performance-related funding for teaching based on preclinical institutes, clinical-theoretical institutes teaching assessments. Beyond this, in accordance and clinical departments. In the underlying with recommendations of the German Research assessment publication performance and acquired Council, the school will enter into the concept of research funding are taken into account in equal performance-related funding for the promotion of proportions, extending over the past three years young researchers and into a performance-related respectively. Thereby research funding granted after allocation of research and office space (LOF). In the an external review process is taken into account in context of the LOF each institute will at first receive full. Research funding granted without an external a parameter-based basic provision of research space review process, e.g. funding from industry, is taken (laboratory space). On a strictly temporary basis this into account with only 30 percent. Total expenditure basic provision of institutes will be supplemented by of research funding per year is used for the the dean’s office taking into account proven calculation. Publication performance is quantified by research activities (e.g. third-party funded the Journal Impact Factor (JIF) of the respective personnel). The re- maining research and office journal of all published original papers. Thereby first- space will be allocated on a flexible basis by the and last autorship rate with one third of the JIF each, dean’s office for currently funded research projects. the remaining third of the JIF is divided between all middle authors.
Behring Non-public Funding by Total Year DFG DFG/SFB FRG EU State Sponsors Foundation Röntgen Funding UKGM Funding Foundation 2004 4.032.335 € 1.630.162 € 3.644.248 € 1.442.817 € 58.464 € 124.088 € 2.556.641 € 4.383.886 € 17.872.642 € 2005 3.437.788 € 2.433.628 € 2.234.492 € 937.891 € 187.710 € 169.522 € 2.022.637 € 4.906.584 € 16.330.253 € 2006 3.371.680 € 2.801.772 € 2.498.489 € 2.688.742 € 53 € 78.717 € 1.713.270 € 3.726.259 € 16.878.982 € 2007 3.558.746 € 4.109.933 € 2.621.109 € 1.685.985 € 11.789 € 175.683 € 1.511.093 € 5.151.000 € 490.963 € 19.316.300 € 2008 3.042.045 € 6.079.496 € 2.339.280 € 1.455.641 € 215.079 € 451.192 € 1.387.533 € 5.944.309 € 133.269 € 809.573 € 21.857.417 € 2009 3.094.743 € 4.902.592 € 2.380.916 € 1.251.064 € 224.920 € 404.231 € 1.834.115 € 5.181.587 € 484.088 € 654.282 € 20.412.537 € 2010 3.471.788 € 5.460.609 € 3.080.677 € 605.496 € 231.253 € 304.433 € 1.789.218 € 4.826.912 € 878.766 € 869.794 € 21.518.945 € 2011 3.665.755 € 6.282.114 € 3.470.365 € 1.466.384 € 170.246 € 243.214 € 1.450.148 € 4.946.463 € 1.204.043 € 1.131.638 € 24.030.371 € 2012 4.195.624 € 5.911.137 € 5.181.860 € 1.269.939 € 263.910 € 2.290.054 € 1.540.889 € 4.651.717 € 913.381 € 1.282.965 € 27.501.475 € 2013 3.493.985 € 6.209.817 € 4.784.043 € 1.822.795 € 276.241 € 388.782 € 1.750.293 € 4.642.531 € 1.129.849 € 988.635 € 25.486.972 € 2014 3.307.062 € 5.256.919 € 3.417.940 € 2.230.347 € 267.212 € 742.442 € 1.886.264 € 4.231.120 € 886.285 € 1.032.654 € 23.258.245 €
Table 1 Development of research funding from 2004 to 2014 in different funding categories
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Fig. 6 Development of total research funding from 2004 to 2014
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Preclinical Institutions
Institute of Anatomy and Cell Biology
Research Group Professor R. Kinscherf Title Die Bedeutung parakrin freigesetzter Zytokine Main fields of research adulter kardialer Progenitorzellen für das Remodelling des insuffizienten Herzens Arteriosclerosis: Novel biomarkers in the blood Principalinvestigator(s) Maxeiner, Wenzel, M Bette, • Development and progression of Arteriosclerosis Weigand, R Kinscherf, Böningand Schlüter • Role of GDF-15 in Arteriosclerosis Summary Das beantragte Projekt hat zum Ziel, ein • Signal transduction of oxLDL besseres Verständnis über die kardiale Wirkung Transfer of anti-angiogenic genes in Morris parakriner Substanzen, die von CPCs freigesetzt hepatoma: Molecular Mechanisms werden, zu ermöglichen. Als Arbeitshypothese wird • Signal transduction in tumor cachexia postuliert, dass die mögliche kardioprotektive • Molecular mechanisms of the anti-inflammatory, Wirkung solcher Substanzen durch eine gezielte anti-proliferative and pro-apoptotic effects of Interaktion verbessert werden kann und dass diese phytopharmaka Wirkung auf das chronisch druckbelastete Herz • The plasma membrane Ca2+-ATPase 2 (PMCA2) in abgestimmt werden muss. breast cancer Funded by von Behring-Röntgen-Foundation
Funding period2012 – 2014 Research projects Title Hepatic factors of tumor cachexia: Metabolom- Title In vitro investigations of the possible protective Analyses, 31P-MR-Spectroscopy, as well as gene effects of krill oil against lipopolysaccharide expression in perivenous and periportal hepatocytes (LPS)treatment of human monocytes and in Kupffer cells Principal investigator R. Kinscherf Principal investigator(s) R. Kinscherf, W. Summary The aim of the in vitro investigation is to Hildebrandt, G. A. Bonaterra, M. Schäfer, V. determine the possible beneficial effects of krill oil Fendrich, A. Kießling (KO) in neutralizing lipopolysaccharide (LPS) or LPS Summary More than 50% of all tumor patients binding. experience tumor cachexia (sarkopenia), which Funded byB.Braun Melsungen AG (via TransMIT inversely influences quality of life and mortality. GmbH) Early alterations of liver metabolism during Funding period 2013 – 2014 sarcopenia – especially the negative nitrogen balance – are not clear. The aim of the study is to Title Cytoprotective effects and impact on neuronal investigate the role of the liver during sarcopenia plasticity of STW 3-VI (St. John's wort) in vitro using an animal model, as well as human biopsies. Principal investigator R. Kinscherf Funded by UKGM – University Medical Centre Summary The aim of our in vitro investigations is to Giessen/Marburg determine the cytoprotective effects and impact on Funding period 2011-2013 neuronal plasticity of STW 3-VI (St. John's wort) against cytotoxic substances. Title Obstructive sleep apnoea syndrome (OSAS): Funded by Steigerwald GmbH (via TransMIT GmbH) Microcirculatory and metabolic changes of skeletal Funding period 2014 – 2016 muscles Principal investigator(s) W.Hildebrandt, R. Schulz, U. Title In vitrocytoprotective effects of omega-3 fatty Koehler, N. Weissmann acids against cytotoxic drugs on human Summary Hypoxia/Reoxygenation stress during hepatocellular carcinoma cells,human kidney obstructive sleep apnoea syndrome (OSAS) is proximal tubule, murine intraglomerularmesangial suggested to be the reason for endothelial or human lung adenocarcinoma cells. dysfunction and insulin resistance, which may result Principal investigator R. Kinscherf in loss of efficiency of heart and skeletal muscle. The Summary The aim of our in vitro investigations is to aim of the study is to investigate molecular determine the cytoprotective effects of omega-3 mechanisms of a reduced function of skeletal muscle fatty acids against cytotoxic drugs on human during OSAS using an animal model, as well as hepatocellular carcinoma cells,human kidney human biopsies. proximal tubule, murine intraglomerularmesangial Funded by von Behring-Röntgen-Foundation or human lung adenocarcinoma cells. Fundingperiod 2011-2013
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Preclinical Institutions
Funded by B.Braun Melsungen AG (via TransMIT Research Group Professor E.Weihe GmbH) PD Dr. Michael Bette; Dr. Mirjam Bertoune; PD Dr. Funding period 2014 – 2015 Burkhard Schütz; Dr. Martin K.-H. Schäfer; PD Dr. Most important publications Reiner Westermann Mey L, Hörmann M, Schleicher N, Reuter P, Dönges S, Kinscherf R, Gassmann M,Gerriets T, Al-Fakhri N Main fields of research (2013)Neuropilin-1 modulates vascular endothelial Chemical coding of neurotransmission and growth factor-induced poly(ADP-ribose)-polymerase neuroendocrine secretion leading to reduced cerebrovascular apoptosis. Molecular and cellular mechanisms of preclinical Neurobiol Dis 59:111-25 and clinical pain
Schwarz A, Wennemuth G, Post H, Brandenburger T, Inflammation Aumüller G, Wilhelm B (2013). Vesicular transfer of Neuroinfection(rabies, HIV/SIV encephalitis) membrane components to bovine epididymal Neuroimmune interactions and spermatozoa.Cell Tissue Res 353(3):549-61 neurodegeneration (amyotrophic lateral sclerosis; Parkinson´s disease) Bonaterra GA, Kelber O, Weiser D, Kinscherf R Neuropeptide signaling and pathophysiology; (2013) Mechanisms of the anti-proliferative and anti- biological effects of ozone in cancer research inflammatory effects of the herbal fixed combination ® Specialities: Core facility for molecular histology STW 5 (Iberogast ) on colon adenocarcinoma (HT29) and laser microdissection (Schäfer/Weihe); cell- cells in vitro. Phytomedicine 20:8-9 specific gene expression profiling; transgenic Schober A, Parlato R, Huber K, Kinscherf R, mouse models relevant for research on infection, Hartleben B, Huber TB, Schütz G, Unsicker K (2013) inflammation, pain, cancer, diabetes and Cell loss and autophagy in the extra-adrenal neurodegeneration chromaffin organ of zuckerkandl are regulated by gluccocorticoidsignalling. J Neuroendocrinol 25 (1): Research projects 34-47 Title VMAT2 as a target for imaging of beta-cell mass Rossmann A, Mandic R, Heinis J, Hoeffken H, Principal investigator(s) E. Weihe and M. Schäfer Kuessner O, Kinscherf R, Weihe E, Bette M (2014) Summary The main aim of the project was to Intraperitoneal oxidative stress in rabbits with evaluate species-specific expression patterns of the papillomavirus-associated head and neck cancer vesicular monoamine transporter 2 (VMAT2) in induces tumoricidal immune response that is primate, pig and rodent pancreatic beta-cells, nerves adoptively transferable. ClinCancer Res 20(16):4289- and mast cells and to generate a new transgenic 301 mouse model for beta-cell imaging with
tetrabenazine based VMAT2 radioligands. Kunz P, Fellenberg J, Moskovszky L, Sápi Z, Krenacs T, Funded by EU (FP7/2007-2013) Poeschl J, Lehner B, Szendrõi M, Ewerbeck V, Funding period 2008-2013 Kinscherf R, Fritzsching B (2014) Osteosarcoma microenvironment: whole-side imaging and Title Influence of the gene deficiency for calcitonin- optimized antigen detection overcome majoer gene related peptide alpha and pituitary limitations in immunohistochemical quantification. adenylatecyclase activating peptide on the in vivo PLoS One 9(3):e90727 rabies virus infection Farhat A, Malecki E, Bonaterra GA, Röthlein D, Wolf Principal investigator(s) M.Bertoune M, Schmitt J, Rosemeyer H, Kinscherf R (2014) Summary Aim of the project is to elucidate Cytostatic/Cytotoxic effects of 5-flourouridine mechanisms for the biological effect of CGRPa and nucleolipids on colon, hepatocellular and renal PACAP during infection with rabies virus in the carcinoma cells: in vitro identification of a potential mouse model. cytotoxic multi-anticancer drug. Funded by UKGM – University Medical Centre ChemBiodivers11(3):469-82 Giessen/Marburg Funding period 2012-2013 Stern-Straeter J, Bonaterra GA, Juritz S, Birk R,
Goessler UR, Bieback K, Bugert P, Schultz J, Hörmann Title Characterization of an astrocyte population K, Kinscherf R*, Faber A* (2014)Evaluation of the susceptible for rabies virus effects of different culture media on the myogenic Principal investigator(s) M. Bertoune differentiation potential of adipose tissue- or bone SummaryAim of the project is to identify the marrow human mesenchymal stem cells. Int J Mol molecular prerequisites that make a regionally Med 33(1):160-70(* both are senior authors) defined population of fibrillary astrocytes in the
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Preclinical Institutions murine brain vulnerable to a mutated rabies virus Title Impact of paracrine released cytokines for the vaccine strain. remodeling of the insufficient heart Funded by Kempkes Foundation Principal investigator(s) R.Maxeiner, Wentzel and Funding period 2012-2013 M. Bette Summary Aim of this project is to proof the Title Involvement of peptidergic signaling pathways hypothesis that human cadial progenitor cells (CPC) in ALS pathogenesis in human patients exhibit it´s therapeutic potential on remodeling and Principal investigator(s) C. Ringer regeneration of the heart by the release of several Summary The disruption of the signaling pathways cytokines. Main factors, identified by its potential to of PACAP and CGRP by genetic depletion resulted in positively influence cardiac muscle contraction in a decelerated disease progression in the SOD1 vitro, are GDF-15, IL-6, IL-8, TIMP-1, and MCP-1. The mouse model of ALS. This study investigates if the impact of these factors on remodeling of the heart two neuropeptides also influence ALS disease and on hypertension should be characterized in an in progression in humans. vivo rat model. Funded by Kempkes Foundation Funded by Von-Behring-Röntgen Foundation Funding period 2012-2013 Fundingperiod 2012-2014
Title Mechanisms responsible for the selective Title German Lung Center (Deutsches Lungen- vulnerability of CGRP expressing motoneurons in zentrum, DLZ amyotrophic lateral sclerosis Principal investigator(s) E. Weihe Principal investigator(s) C. Ringer Summary The aim is to decipher the neuroimmune Summary This study is based on the observation, anatomy and role of neuropeptide and classical that motoneurons expressing the neuropeptide transmitter signaling in inflammatory and allergic CGRP selectively degenerate, whereas motoneurons airway diseases by using neuropeptide and without CGRP expression seemed to be resistant in neuropeptide receptor gene deficient mouse models the SOD1 mouse model of ALS. The aim is to clarify (gene deficiencies for PACAP, PAC1, CGRP, RAMP1) the underlying mechanisms of neuronal vulnerability and experimental stress conditions. and resistance, respectively, to ALS pathology. Funded by BMBF – Federal Ministry of Education Funded by German Society for Muscle diseases and Research Funding period 2012-2013 Funding period 2012-2015
Title Regulation of the cholinergic gene locus in keratinocytes Most important publications Principal investigator(s) B. Schütz and E. Weihe Ringer C,Büning LS, SchäferMK, Eiden LE, Weihe E, Summary The cholinergic gene locus (CGL) encodes Schütz B (2013) PACAP signaling exerts opposing two genes for proper cholinergic neuron function, effects on neuroprotection and neuroinflammation i.e. choline acteyltransferase (ChAT) needed for the during disease progression in the SOD1(G93A) production of acetylcholine (ACh), and the vesicular mouse model of amyotrophic lateral sclerosis. acetylcholine transporter (VAChT) for regulated Neurobiol Dis 54C:32-42 import of ACh into synaptic vesicles. We hypothesize that the transcriptional regulation of the CGL in the Schäfer MK, Hartwig NR, Kalmbach N, Klietz M, production and sequestration of keratinocyte ACh Anlauf M, Eiden LE, Weihe E (2013) Species-specific essentially differs from that found in neurons. In our vesicular monoamine transporter 2 (VMAT2) project we thus aim to elucidate the regional, skin expression in mammalian pancreatic beta cells: layer- and cell-specific activity of the CGL under implications for optimising radioligand-based human physiological and pathophysiological situations (e.g. beta cell mass (BCM) imaging in animal models. Inflammation, barrier function disturbances) in Diabetologia56: 1047-1056 humans and rodent (mouse, rat) model systems, and Makarova G, Bette M, Schmidt A, Jacob R, Cai C, the possibility of CGL regulation by exogenously Rodepeter F, Betz T, Sitterberg J, Bakowsky U, Moll applied substances using state of the art R, Neff A, Sesterhenn A, TeymoortashA, Ocker M, technologies (e.g. laser capture microdissection, Werner JA, Mandic R (2013) Epidermal growth qRT-PCR, in situ hybridization, transcriptome factor-induced modulation of cytokeratin expression profiling). levels influences the morphological phenotype of Funded by LOEWE-Research Focus Giessen, head and neck squamous cell carcinoma cells. Cell Marburg, Frankfurt, “Non-neuronal cholinergic Tissue Res 351:59-72 Systems”, Project B3 Funding period 2012-2014 Krieg A, Mersch S, Boeck I, Dizdar L, Weihe E, Hilal Z, Krausch M, Möhlendick B, Topp SA, Piekorz RP,
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Preclinical Institutions
Huckenbeck W, Stoecklein NH, Anlauf M, KnoefelWT the translational level and localized at the cellular (2014) Newmodel for gastroenteropancreatic large- level by specific antibodies to distinct cell types and cell neuroendocrine carcinoma:establishment of two functional membrane domains in the clinically relevant cell lines. PLoS One 9(2):e88713 gastrointestinal tract.
Deckmann K, Filipski K, Krasteva-Christ G,Fronius M, Research projects Althaus M, Rafiq A, Papadakis T, Renno L, Jurastow I, Wessels L, Wolff M, Schütz B, Weihe E, ChubanovV, Title Expression and cellular localization of guanylin Gudermann T, Klein J, Bschleipfer T, Kummer W and uroguanylin and their functional coupling (2014) Bitter triggers acetylcholine release from proteins in the rat kidney polymodal urethral chemosensory cells and bladder Principal investigator(s) K. Schwabe&Y. Cetin reflexes. ProcNatlAcadSci U S A 111(22):8287-92 SummaryThis work demonstrates the expression and cellular localization of two related peptides Rossmann A, Mandic R, Heinis J, Hoeffken H, guanylin and uroguanylin, their receptor Kuessner O, Kinscherf R, Weihe E, Bette M guanylatecyclase C, as well as to the downstream (2014)Intraperitoneal oxidative stress in rabbits with signaling and effector proteins, i.e. protein kinase GII papillomavirus-associated head and neck cancer (Prkg2), CFTR, and the solute carrier family 4, anion induces tumoricidalimmuneresponse that is exchanger, member 2 (Slc4a2) in the kidney of the adoptively transferable. Clin Cancer Res20(16):4289- rat.Guanylin, uroguanylin as well as Gucy2c, Prkg2, 301 and CFTR are restricted to the epithelial cells of the tubules system in the renal cortex and in the inner Panneck AR, Rafiq A, Schütz B, Soultanova A, stripes of the outer medulla (ISOM). Whereas Slc4a2 Deckmann K, Chubanov V, Gudermann T, Weihe E, displayed an opposed distribution pattern; strong Krasteva-Christ G, Grau V, Del Rey A, Kummer W immunoreactivities in the tubule system of the (2014) Cholinergic epithelial cell with chemosensory cortex and in the inner medulla and no localization in traits in murine thymic medulla. Cell Tissue Res the ISOM.We assume that guanylin/uroguanylin are 358(3):737-48 synthesized in the tubules system of the kidney and were luminally secreted into the urine,which Schütz B, Schäfer MK, Gördes M, Eiden LE, Weihe E activates the downstream signaling cascade as (2014) Satb2-Independent Acquisition of the already described for the intestine. Cholinergic Sudomotor Phenotype in Rodents. Cell MolNeurobiol 2014 Sep 20 [Epub ahead of print] Research group Professor B. Steiniger
Research group Professor Y. Cetin Main fields of research 1. Cell kinetics of the monocyte-macrophage Main fields of research system in rats It is well-known that heat-stable enterotoxins 2. Phenotype of lymphocytes, dendritic cells, produced by Escherichia coli cause severe diarrhea endothelia and stromal cells in human primary that is a problem in various developing countries. and secondary lymphatic organs These toxins activate a guanylatecyclase C-receptor 3. Three-dimensional reconstruction of localized in the mucous membrane of the microvessels by means of serial sections gastrointestinal tract. Since the discovery of 4. Cell composition of the human dental pulp and guanylin, an endogeneous peptide isolated from the bone marrow intestine and highly homologous to the short toxin peptides, it became obvious that this peptide is the Research projects true ligand of the of the guanylatecyclase C-receptor. Title Analysis of capillary sheaths and three- To study the functional role of guanylin with regard dimensional reconstruction of microvessels in to regulation of electrolyte/water secretion in the human spleens intestine, the working group analyzed various Principal investigator B.Steiniger cellular signaling and effector proteins involved in Summary The human splenic microvasculature is guanylin action. Using molecular biology, composed of arterioles, capillaries, venous sinuses immunochemical and immunohistochemical and venules. Certain splenic capillaries are covered techniques, the expression of guanylin, guanylin- by so-termed capillary sheaths of unknown cellular receptor guanylatecyclase C (GC-C), cystic fibrosis composition. We demonstrate that capillary sheaths transmembrane conductance regulator (CFTR-) consist of endothelial cells, pericytes, specialized protein, cGMP-dependent Proteinkinase GII (cGKII), stromal sheath cells, macrophages and B- and at least an anion exchanger type 2 (AE-2) was lymphocytes. Capillary sheaths and periarteriolar studied. Moreover, these proteins were detected at regions belong to the splenic B-lymphocyte
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Preclinical Institutions compartment scaffolded by phenotypically distinct stromal cells.
S100+ Schwann cells and CD34+ endothelial cells in arteriole/nerve associations of a human molar dental pulp. 25 µm-thick undecalcified ground tooth section CD271+ stromal cells (blue) and CD20+ B-lymphocytes (brown) forming a human splenic capillary sheath Most important publications Title Stromal cells of T- and B-cell regions in human Steiniger BS, Bubel S, Böckler W, Lampp K, Seiler A, spleens Jablonski B, Guthe M, Stachniss V (2013) Principal investigator B. Steiniger Immunostaining of pulpal nerve fibre Summary We define the phenotype of a so far bundle/arteriole associations in ground serial unknown third stromal cell type of the human sections of whole human teeth embedded in splenic white pulp which exists in addition to Technovit® 9100. Cells Tissues Organs 198:57-65 fibroblastic reticulum cells of T-lymphocyte zones and follicular dendritic cells of B-lymphocyte follicles. Steiniger BS, Seiler A, Lampp K, WilhelmiV, Stachniss This third cell type is located at the surface of the V (2014) B lymphocyte compartments in the human white pulp, especially at the surface of follicles, and splenic red pulp: capillary sheaths and periarteriolar expresses the mucosal cell adhesion molecule regions. Histochem Cell Biol 141: 507-518
MAdCAM-1. Steiniger BS, Wilhelmi V, Seiler A, Lampp K, Stachniss V (2014) Heterogeneity of stromal cells in Title Microscopic anatomy of the human bone the human splenic white pulp. Fibroblastic reticulum marrow cells, follicular dendritic cells and a third superficial Principal investigator(s) B. Steiniger, V. Stachniss stromal cell type. Immunology 143:462-477 and V. Wilhelmi Summary In cooperation with the clinics of orthopaedics and of orofacial surgery a special procedure for embedding large undecalcified bone marrow specimens (femoral head, iliac crest) in a General information about the institute special methacrylate was established. Using this method, undecalcified serial bone sections may be Research funding 255.365,91 € cut with a conventional microtome, stained by immunohistological procedures and reconstructed in three dimensions. Contact Details: Robert-Koch-Str. 8, 35037 Marburg, Title Microanatomy of the human dental pulp Tel.:++49 (0) 6421-28 66248 Principal investigator(s) B. Steiniger& V. Stachniss Director: Professor Dr. Eberhard Weihe Summary The arrangement of nerves and arterioles in the dental pulp of human molars was reconstructed from serial ground sections. The majority of dental pulp arterioles were found embeddded in myelinized nerve fibre bundles.
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Preclinical Institutions
Institute of Molecular Biology and Tumorbiology
Research Group Professor R. Müller transcription factors in a dominant manner via an and the associated research group of Dr. Matthias unknown mechanism; this is being investigated with Lauth biochemical and genetic means. In vitro data derived from primary human stromal cell cultures shows that Main fields of research these novel ligands are promising candidates for Rolf Müller’ research projects are focused on clinical use in targeted approaches against neoplastic signaling networks and transcriptional regulation in and metabolic pathophysiological states. human ovarian cancer in the context of therapy Funded by DFG – German Research Foundation resistance, the tumor microenvironment and tumor Funding period 2013 – 2016 metabolism (cooperation with Drs. Silke Reinartz and Uwe Wagner, Clinic for Gynecology). In addition, the Title Suppression of oncogenic signaling and group works on mechanisms of transcriptional inhibition of cancer cell invasion by inhibition of regulation by the nuclear receptor PPARβ/δ, in PPARβ/δ particular its role in macrophage polarization, its Principal investigator(s) R. Müller, D. Brandt & R. interaction with cytokine signaling pathways and the Grosse, Pharmacological Institute evaluation of the therapeutic potential of newly Summary Besides its established functions in developed inhibitory ligands. intermediary metabolism and developmental processes, the nuclear receptor PPARβ/δ plays a less Matthias Lauth’s work is centered on the regulation defined role in tumorigenesis. We identified a and role of the Hedghog signaling pathways in tumor function for PPARβ/δ in cancer cell invasion. We cells and their crosstalk with the tumor stroma. found that nhibitory ligands for PPARβ/δ strongly diminish the serum- and TGFβ-induced invasion of Research projects MDA-MB-231 human breast cancer cells into a Title Chromatin regulation by the nuclear receptor three-dimensional matrigel matrix. ChIP-Seq and PPARβ/δ transcriptome analyses identified which identified Principal investigator(s) R. Müller the gene encoding angiopoietin-like 4 (ANGPTL4) as Summary The ligand-regulated nuclear receptor the major transcriptional PPARβ/δ target in these peroxisome proliferator-activated receptor β/δ cells. We could also show that repression of (PPARβ/δ) can both activate and repress ANGPTL4 transcription by inverse PPARβ/δ agonists transcription, but the regulation, mechanistic is functionally linked to the inhibition of cancer cell principles and biological consequences of these invasion into a three-dimensional matrix. These functions are only partly understood. By using a findings indicate that a PPARβ/δ – ANGPTL4 pathway combination of chromatin immunoprecipitation is involved in the regulation of tumor cell invasion (ChIP) sequencing and transcriptional profiling we and that its pharmacological manipulation by inverse have defined distinct types of transcriptional PPARβ/δ agonists is feasible. responses of target genes to PPARβ/δ ligands or Funded by DFG, SFB TRR17 – German Research PPARβ/δ depletion. Elucidation of the molecular Foundation, Transregional Collaborative Research basis of these distinct target gene responses is the Centre 17 goal of this project. Funded period 2004 – 2013 Funded by DFG – German Research Foundation Funded period 2011 – 2015 Title Regulation of IL-1β signaling by cytoplasmic PPARβ/δ Title Design, synthesis, and molecular Principal investigator R. Müller characterisation of selective inverse agonists and Summary In cooperation with M. Kracht's group antagonists of PPARβ/δ (Gießen) we discoverd an unexpected cytoplasmic Principal investigator(s) T. Adhikary & W. Diederich, function of PPARβ/δ. We found that silencing of Institue of Pharmaceutical Chemistry PPARβ/δ expression interfered with the expression Summary We developed highly specific inverse of a large subset of interleukin-1β (IL-1β)-induced agonists and antagonists of the nuclear receptor target genes in HeLa cells, which was preceded by an PPARb/d. The binding mode and induced inhibition of the IL-1β-induced phosphorylation of conformational changes of the receptor are TAK1 and its downstream effectors, including the elucidated by X-ray crystallography, and specificity NFκBα inhibitor IκBα (NFKBIA) and the NFκBα and bioavailability of the compounds are optimized. subunit p65 (RELA). PPARβ/δ enhances the The inverse agonists block the upregulation of interaction between TAK1 and the small heat-shock transcription of PPARb/d target genes by other
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Preclinical Institutions protein HSP27, a known positive modulator of TAK1- PPARβ/δ agonists. These observations suggest that mediated IL-1β signaling. Our observations suggest the deregulation of PPARβ/δ target genes by ligands that PPARβ/δ plays a role in the assembly of a of the tumor microenvironment contributes to the cytoplasmic multi-protein complex containing TAK1, pro-tumorigenic polarization of ovarian carcinoma TAB1, HSP27 and PPARβ/δ, and thereby participates TAMs. This conclusion is supported by the in the NFκB response to IL-1β. association of high ANGPTL4 expression with a Funded by DFG – German Research Foundation shorter relapse-free survival in serous ovarian Funding period 2011 – 2015 carcinoma. Funded by Sander Foundation Title Phenotype and clinical relevance of ascites- Funded period 2012 – 2014 associated macrophages in human ovarian carcinoma Title Regulation of Hedgehog signaling by the Principal investigator(s) S. Müller-Brüsselbach & S. DYRK1B kinase Reinartz, Clinic for Gynecology Principal investigator(s) M. Lauth Summary Ovarian cancer is typically accompanied by Summary The aim of this project has been to the occurrence of malignant ascites containing large investigate how the tumor-associated DYRK1B kinase number of macrophages. It has been suggested that affects mammalian Hedgehog signaling. The group these tumor-associated macrophages (TAMs) are could show that Dyrk1b functions as a negative skewed to alternative polarization (M2) and thereby regulator of the pathway. Furthermore, a molecular play an essential role in therapy resistance and framework and a pathophysiological function for this immune suppression. We have investigated the interaction could be established. nature, regulation and clinical correlations of TAM Funded by DFG – German Research Foundation polarization in serous ovarian cancer. Although Funded period 2010 – 2013 surface expression of the M2-marker CD163 on TAMs was inversely associated with relapse-free Title Evaluation of DYRK1A kinase as a therapeutic survival (RFS), global gene expression profiles target in pancreatic carcinoma revealed a mixed-polarization phenotype unrelated Principal investigator M. Lauth to the M1/M2 classification. CD163 surface Summary Previous work suggests an oncogenic role expression also correlated with the ascites levels of of the DYRK1A kinase in Hedgehog-driven IL-6 and IL-10, both cytokines induced CD163 malignancies. In the present project, our group expression, and their ascites levels showed a clear investigates the molecular mechanisms of the inverse association with RFS. These findings define a Hedgehog-DYRK1A relationship and the impact of subgroup of patients with high CD163 expression, this crosstalk on the pathway activity in normal and high IL-6 and/or IL-10 levels and poor clinical in cancer cells. outcome. Funded by Deutsche Krebshilfe Funded by Sander Foundation and UKGM – Funding period 2011 – 2015 University Hospital Giessen and Marbug Funded period 2012 – 2014 Title Inhibition of Notch and/or Hedgehog signaling pathways in the therapy of fibrosis Title Function and therapeutic potential of PPARβ/δ Principal investigator M. Lauth in tumor-associated macrophages in human ovarian Summary Both, Hedgehog and Notch signaling are carcinoma involved in the development of several fibrotic Principal investigator(s) S. Müller-Brüsselbach, T. conditions, but their functional interaction remains Adhikary & S. Reinartz, Clinic for Gynecology poorly understood. In collaboration with the group Summary To elucidate its function of PPARβ/δ in of Dr. Borggrefe (Institute of Biochemistry, Uni tumor-associated macrophages (TAMs) we Gießen) we are investigating the mechanisms of determined the PPARβ/δ-regulated transcriptome Hedgehog-Notch crosstalk in order to understand and cistrome for TAMs from ovarian carcinoma the cellular interactions between these two patients. Comparison with monocyte-derived pathways. macrophages showed that the vast majority of direct Funded by UKGM – University Hospital Giessen and PPARβ/δ target genes are upregulated in TAMs and Marburg largely refractory to synthetic agonists, but Funding period 2013 – 2015 repressible by inverse agonists. These include cell type-selective genes associated with immune Title GLI transcription factors: A suitable target regulation and tumor progression Lipidomic analysis structure in the future therapy of pancreatic cancer? of malignancy-associated ascites revealed that this Principal investigator M. Lauth deregulation is caused by high concentrations of Summary The Hedgehog pathway and its final polyunsaturated fatty acids acting as potent effectors, the GLI proteins, have been implicated in
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Preclinical Institutions the etiology of pancreatic cancer. However, the Most important publications relevance of Hedgehog/GLI in tumor cells versus the AG Müller stroma is not clear. In this project, we have Stockert J, Wolf A, Kaddatz K, Schnitzer E, elucidated novel and unexpected tumor-halting Finkernagel F, Meissner W, Müller-Brüsselbach S, functions of GLI1 in pancreatic cancer cells, raising Kracht M, Müller R (2013) Regulation of TAK1/TAB1- questions about the utility of a Hedgehog/GLI mediated IL-1β signalling by cytoplasmic PPARβ/δ. directed therapy in this type of cancer. In line with PLoS ONE 8(4):e63011 our data, in vivo results from mouse models and patient data have led to the abortion of clinical trials Adhikary T, Brandt DT, Kaddatz K, Stockert J, using Hedgehog inhibitors in pancreatic cancer. Finkernagel F, Naruhn S, Meissner W, Obert J, Lieber Funded by UKGM – University Hospital Giessen and S, Scharfe M, Jarek M, Toth PM, Scheer F, Diederich Marburg WE, Reinartz S, Grosse R, Müller-Brüsselbach S, Funding period 2012 – 2014 Müller R (2013) Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit Title Evaluating novel target structures in the cancer cell invasion. Oncogene 32:5241-5252 therapy of lung fibrosis Principal investigator M. Lauth Adhikary T, Müller R (2013) In vivo studies of PPAR- Summary Hedgehog signaling is involved in the chromatin interactions: chromatin immune- development of lung fibrosis, but its role is not well precipitation for single-locus and genome-wide defined. In collaboration with the group of Dr. analyses. Meth Mol Biol 952: 175-185 Wygrecka (Institute of Biochemistry, Uni Gießen) we are investigating the Hedgehog pathway in lung Reinartz S, Schumann T, Finkernagel F, Wortmann A, fibrosis and test novel targeting approaches to Jansen JM, Meissner W, Krause M, Schwörer A-M, combat this disease. Wagner U, Müller-Brüsselbach S, Müller R (2014) Funded by von Behring Röntgen Foundation Mixed-polarization phenotype of ascites-associated Funding period 2014 – 2016 macrophages in human ovarian carcinoma: correlation of CD163 expression, cytokine levels and Title Novel ciliary regulatory circuits in Hedgehog- early relapse. Int J Cancer 134: 32-42 dependent tumor entities Principal investigator M. Lauth AG Lauth Summary The primary cilium is crucial for proper Tariki M, Wieczorek SA, Schneider P, Bänfer S, Hedgehog signaling. However, the Hedgehog- Veitinger S, Jacob R, Fendrich V, Lauth M (2013) RIO induced molecular mechanisms within primary cilia kinase 3 acts as a SUFU-dependent positive regulator are currently not well resolved. In this project, we of Hedgehog signaling. Cell Signal 25(12):2668-75 characterize novel ciliary candidate molecules which we have previously identified and test their Tariki M, Dhanyamraju PK, Fendrich V, Borggrefe T, relevance in Hedgehog-driven cancer, such as Feldmann G, Lauth M (2014) The Yes-associated medulloblastoma. protein controls the cell density regulation of Funded by DFG – German Research Foundation Hedgehog signaling. Oncogenesis 3:e112 Funding period 2013 – 2016 Knoop RF, Sparn M, Waldmann J, Plassmeier L, Title Therapy of medulloblastoms (Research award) Bartsch DK, Lauth M, Hudemann C, Fendrich V. Principal investigator M. Lauth (2014) Chronic Pancreatitis and Systemic Summary Medulloblastoma is the most frequent Inflammatory Response Syndrome Prevent Impact of malignant brain tumor in children and a large Chemotherapy with Gemcitabine in a Genetically fraction of this cancer grows in a Hedgehog- Engineered Mouse Model of Pancreatic Cancer. dependent manner. Current selective therapies Neoplasia 16(6):463-70 target the Hedgehog pathway component Smoothened, leading to good clinical responses but Dhanyamraju PK, Holz PS, Finkernagel F, Fendrich V, also to the development of drug-resistant clones, Lauth M (2014) Histone deacetylase 6 represents a necessitating the need to identify additional drug novel drug target in the oncogenic Hedgehog targets. In this project, we have identified HDAC6 as signaling pathway. Molecular Cancer Therapeutics; in an overexpressed gene in medulloblastoma and press characterized this protein a novel drug target in the oncogenic Hedgehog signaling pathway. Funded by Stiftung Tumorforschung Kopf-Hals, Römerwaldklinik Funding period since 2014
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Research Group Professor A. Brehm Funded by DFG – German Science Foundation, Research Grant 2102/6-2 Main fields of research Funded period 2013 – 2016 Chromatin structure plays an important role in regulating the activity of eukaryotic genomes in both Title IRTG 1384 Project healthy and diseased cells. We investigate enzymes Principal investigator(s) A. Brehm and protein factors that establish, modulate and Summary We have analysed the functional and maintain chromatin structures to regulate gene physical interactions between the chromatin expression by using biochemical and genomic remodeler dMi-2 and the nuclear hormone receptor approaches. EcR. Funded by DFG, International Research Training Research projects Group/IRTG 1384: Enzymes and multienzyme complexes acting on nucleic acids Title ATP-dependent chromatin remodeling Funded period 2011 – 2015 complexes in Drosophila, TR81 Project A1
Principal investigator(s) A. Brehm Summary We have unraveled molecular mechanisms that recruit the ATP-dependent Most important publications Chromatin remodeler dMi-2 to stress-induced genes. Meier K, Brehm A (2014) Chromatin regulation: How This work has uncovered an unexpected role of Poly- complex does it get? Epigenetics 9(11): 1485-95 ADP-Ribose and RNA in guiding dMi-2 to heat shock genes. Bergs JW, Neuendorff N, van der Heijden G, Funded by DFG, SFB TRR81 – German Research Wassenaar E, Rexin P, Elsässer HP, Moll R, Baarends Foundation, Transregional Collaborative Research WM, Brehm A (2014) Differential expression and sex Centre 81: Chromatin changes in differentiation and chromosome association of CHD3/4 and CHD5 malignancies during spermatogenesis. PLoS One 9(5):e98203 Funded period 2010 – 2014
Title Recruitment mechanisms of the chromatin Research Group Professor G. Suske remodeler dMi-2/CHD4, TR81 Project A1 Principal investigator(s) A. Brehm Main fields of research Summary We are using a comprehensive approach We study physiological and mechanistic aspects of to identify different molecular mechanisms used to members the Sp family of transcription factors, target dMi-2 to chromatin. which are key transcriptional regulators of various Funded by DFG, SFB TRR81 – German Research developmental and cellular processes. Particularly, Foundation, Transregional Collaborative Research we focus on posttranslational modifications and on Centre 81: Chromatin changes in differentiation and chromatin-based mechanisms that determine malignancies specificity of individual Sp family members. Funded period 2014 – 2018 Research projects Title Mechanism of chromatin regulation by the LINT Title Molecular mechanisms of transcriptional complex control by Sp2 Principal investigator(s) A. Brehm Principal investigator(s) G. Suske Summary We have characterised composition and Summary In this project we focus on the function of LINT, a chromatin repressor that contains transcription factor Sp2, which is the least the Drosophila tumour suppressor L(3)mbt and the characterized Sp family member. By the combination corepressor CoREST. of biochemical, molecular biology and cell biology Funded by DFG – German Science Foundation, techniques we aim to obtain mechanistic clues Research Grant 2102/6-1 towards understanding the mode of action of Sp2. Funded period 2009 - 2013 Funded by DFG – German Research Foundation, Research Grant SU 102/8-1 Title Functional characterisation of LINT and other Funding period 2012 – 2015 CoREST-containing complexes Principal investigator(s) A. Brehm Title Mechanisms of SUMO-dependent gene Summary We are using systematic approaches to silencing identify and characterise dCoREST-containing Principal investigator(s) G. Suske protein complexes that regulate chromatin structure Summary SUMO modification of many transcription and gene activity. factors including Sp3 is linked to transcriptional
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Preclinical Institutions repression. Our previous investigations revealed that Stielow C, Stielow B, Finkernagel F, Scharfe M, Jarek SUMO modification of transcription factors can act M, Suske G (2014) SUMOylation of the polycomb as a molecular beacon for the recruitment of group protein L3MBTL2 facilitates repression of its chromatin-modifying machineries that impose target genes. Nucleic Acids Res 42:3044-3058 epigenetic silencing on target genes. Following the mechanistic clues provided by these findings we analyze further the role of SUMOylation in gene Research Group Professor U. M. Bauer silencing. Funded by DFG, German Research Foundation, Main fields of research Transregional Collaborative Research Centre 81: Protein arginine methyltransferases (PRMTs) play an Chromatin changes in differentiation and important role in the regulation of chromatin malignancies structure and chromatin-dependent processes. In Funding period 2010 – 2014 mammals, the enzymes constitute a family of 9 members (PRMT1-9), which share a conserved Title Recruitment and mechanisms of action of the catalytic domain and perform mono- and di- L3MBTL2-containing non-canonical PRC1 complex methylation of arginine residues in proteins. A Principal investigator(s) G. Suske subgroup of PRMTs methylates histones as well as Summary The polycomb group protein Lethal(3) non-histone chromatin proteins. Like other Malignant Brain Tumor-Like 2 (L3MBTL2) is a subunit chromatin-modifying enzymes, they function as of the non-canonical PRC1.6 complex. Genome-wide transcriptional coregulators, contribute either to analysis of L3MBTL2 occupancy in chromatin activation or repression of gene expression and revealed that L3MBTL2 is predominantly bound to thereby control important cellular processes, such as proximal promoter regions. We aim to analyse the proliferation, differentiation and apoptosis. We wish mode of recruitment to chromatin, and to decipher to elucidate the molecular function of PRMTs in the the repression mechanisms mediated by L3MBTL2 regulation gene expression. and the entire PRC1.6 complex. Funded by DFG, German Research Foundation, Transregional Collaborative Research Centre 81:
Chromatin changes in differentiation and malignancies Research projects Funding period 2014 – 2018 Title Functional analysis of the histone arginine methyltransferase PRMT6, TR81 Project A3 Title Integrated Research Training Group on Principal investigator(s) U. - M. Bauer Epigenetics and Chromatin Summary In our previous work we identified PRMT6 Principal investigator(s) G. Suske as the major mammalian methyltransferase for Summary Within the TRR81, the Integrated Research histone H3 R2. We established that the enzyme Training Group provides a platform for high-level counteract H3 K4 trimethylation and thereby structured training on epigenetics and chromatin transcriptional activation. Important questions, such accompanied by a career development programme. as how PRMT6 is recruited to chromatin, which are The daily research activities of the PhD students are the genome-wide target genes of PRMT6, is PRMT6 complemented by lectures, seminars, courses, part of a multi-subunit corepressor complex, and workshops and retreats including Dutch-German what are the biological functions of PRMT6, are still meetings and exchanges. Particular emphasis is unsolved, which we would like to unravel in this placed on fostering the independence of the PhD project. students. Funded by DFG, SFB TRR81 – German Science Funded by DFG, German Research Foundation, Foundation, Transregional Collaborative Research Transregional Collaborative Research Centre 81: Centre 81, Chromatin changes in differentiation and Chromatin changes in differentiation and malignancies malignancies Funded period 2010 – 2014 Funding period: 2010 – 2014 and 2014 - 2018 Title Transcriptional control by protein arginine methylation Principal investigator(s) U. - M. Bauer Most important publications Summary We are characterizing the functional Diezko R, Suske G (2013) Ligand binding reduces interaction between the chromatin remodeller SUMOylation of the peroxisome proliferator- CDH3/4CHD4 and PRMT4. activated receptor (PPAR) activation function 1 Funded by DFG – German Research Foundation, (AF1) domain. PLoS ONE 8: e66947 Research Grant BA 2292/1-3 Funded period 2013 – 2016
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35043 Marburg Title Epigenetics of the nuclear oncoprotein Ski in Tel.:++49 (0) 6421-28 66237 AML Director: Professor Dr. Rolf Müller Principal investigator(s) U. - M. Bauer, A. Neubauer, S. Stiewe Summary We are characterizing the function of the corepressor Ski in acute myeloid leukemia. Funded by DFG – German Research Foundation, Research Grant SPP1463 Funded period 2012 – 2015
Title Deciphering the role of protein arginine methyltransferases (PRMTs) in lung development and lung cancer. Principal investigator(s) U. - M. Bauer, T. Braun (MPI, Bad Nauheim) Summary We are characterizing the function of PRMT5 in lung development and cancer. Funded by LOEWE priority research program “Lung Center”, Grant Funded period 2013 – 2015
Title Genome-wide mapping of histone modifications in the establishment of disease phenotype pulmonary arterial hypertension Principal investigator(s) U. - M. Bauer, S. Pullamsetti (MPI, Bad Nauheim) Summary We are characterizing the function of HDAC1, 2 and 8 in idiopathic pulmonary arterial hypertension. Funded by LOEWE priority research program “Lung Center”, Grant Funded period 2013 – 2015
Most important publications Streubel G, Bouchard C, Berberich H, Zeller MS, Teichmann S, Adamkiewicz J, Müller R, Klempnauer K-H, Bauer UM (2013) PRMT4 Is a Novel Coactivator of c-Myb-Dependent Transcription in Haematopoietic Cell Lines. PLoS Genet 9, e1003343
General information about the institute
Research funding 3.174.022,55 €
Contact Details: Institute of Biology and Tumor Research (IMT) Emil-Mannkopff-Str. 2 35032 Marburg and Center for Tumor Biology and Immunology (ZTI) Hans-Meerwein-Str. 3
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Institute of Physiological Chemistry
Research Group Professor G. Schratt Funded by DFG, SFB 593 – German Research Foundation, Collaborative Research Centre 593 Main fields of research Funded period 2011 - 2014 Our laboratory is interested in the molecular mechanism of synapse development and plasticity in Title The function of microRNA-dependent mammalian neurons, with a special focus on the role regulation of Ube3a in mammalian synapse of microRNA-dependent control of local mRNA development translation in the synapto-dendritic compartment. Principal investigator(s) G. Schratt, R. Fiore We are studying the function of microRNAs in Summary The aim of this project is to study the Hebbian and homeostatic forms of synaptic plasticity regulation by microRNAs of a neuronal ubiquitin and its implications for memory formation, using ligase (Ube3a) which is mutated in Angelman both primary cell culture and animal models. Syndrome, a neurodevelopmental disorder Moreover, we are investigating the role of aberrant characterized by mental retardation and autism. In microRNA function in neurological diseases particular, we are investigating the regulation of the characterized by synaptic dysfunction, including miR379-410 cluster by a specific Ube3a transcript cognitive impairments, epilepsy and depression. isoform by a ceRNA mechanism. Finally, we are interested in the mechanisms that Funded by UKGM – University Medical Centre control miRNA function at synapses, focusing on Giessen / Marburg activity-dependent miRNA transport and processing. Funded period 2012 - 2014
Research projects Title microRNAs in the pathogenesis, treatment and Title microRNA function in homeostatic plasticity in prevention of epilepsy “EpimiRNA” the mammalian brain Principal investigator(s) G. Schratt Principal investigator(s) G. Schratt Summary The aim of this project is to identify novel Summary The aim of this project is to investigate the miRNAs involved in the development of epilepsy and role of the miR379-410 cluster in homeostatic forms to characterize their mode of action, focusing on the of plasticity in the developing mammalian brain. regulation of synapse structure and function. Using primary neurons, we demonstrated an Moreover, a screening platform will be established important contribution of the miR379-410 cluster to to identify natural compounds with anti- synaptic downscaling (Fiore et al., 2014). We will use epileptogenic activity targeting microRNAs. genetic mouse models to study the effects of Funded by European Union (EU FP7, HEALTH) miR379-410 loss-of-function in experience- Funded period 2013 – 2018 dependent development of the mouse visual cortex and Di George Syndrome mice, a model for Title microRNAs as regulators of neuroplasticity in schizophrenia. affective disorders Funded by European Research Council (EU FP7, Principal investigator(s) G. Schratt Starting Grant) Summary The aim of this project is to identify Funded period 2010 – 2015 microRNAs involved in the regulation of neuronal homeostasis with relevance for affective disorders, Title Molecular mechanisms underlying dendritic including bipolar disorder and major depression. transport and processing of neuronal microRNAs Parallel small RNA sequencing studies in humans and Principal investigator(s) G. Schratt rats are performed to delineate common Summary The aim of this project is to characterize deregulated miRNAs in depressed human subjects the molecular mechanisms that are responsible for and rat models of affective disorders. the regulated trafficking of microRNA precursors to Funded by DFG, FOR2107 – German Research dendrites and for the activity-dependent processing Foundation, Researcher Group 2107 near synapses of hippocampal neurons. We are also Funded period 2014 – 2017 investigating the relevance of these mechanisms for synaptic plasticity. A study describing an RNA- binding protein that is important for the transport of Most important publications the synaptic miR-134 has already been published Bicker S, Khudayberdiev S, Weiss K, Zocher K, (Bicker et al., 2013) Baumeister S, Schratt G (2013) The DEAD-box helicase DHX36 mediates dendritic transport of the neuronal precursor-microRNA-134. Genes Dev
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27:991-996 migration and differentiation, synaptic physiology, and behavior. Khudayberdiev S, Zampa F, Rajman M, Schratt G Funded by UKGM – University Medical Centre (2013) A comprehensive characterization of the Giessen / Marburg nuclear microRNA repertoire of post-mitotic Funded period 2014 – 2015 neurons. Front Mol Neurosci 6:43
Forstner AJ, Degenhardt F, Schratt G, Nöthen MN
(2013) MicroRNAs as the cause of schizophrenia in Most important publications 22q11.2 deletion carriers, and possible implications for idiopathic disease: a mini-review. Front Mol Wolf M, Zimmermann AM, Görlich A, Gurniak CB, Neurosci 6:47 Sassoè-Pognetto M, Friauf E, Witke W, Rust MB (2014) ADF/cofilin controls synaptic actin dynamics Fiore R, Rajman M, Schwale C, Bicker S, Antoniou A, and regulates synaptic vesicle mobilization and Bruehl C, Draguhn A, Schratt G (2014) miR-134- exocytosis. Cereb Cortex, 2014 Apr 25 (Epub ahead dependent regulation of Pumilio2 is necessary for of print) homeostatic synaptic depression, EMBO J 33:2231- 46 Zimmermann AM, Jene T, Wolf M, Görlich A, Gurniak CB, Sassoè-Pognetto M, Witke W, Friauf E, Rust MB Aksoy-Aksel A, Zampa F, Schratt G (2014) microRNAs (2014) ADHD-like phenotype in a mouse model with and synaptic plasticity – a mutual relationship. Phil impaired synaptic actin dynamics. Biol Psychiatry, Trans R Soc Lond B 369:1652 2014 Mar 21 (Epub ahead of print)
Bicker S, Lackinger M, Weiss K, Schratt G. (2014) Kullmann JA, Wickertsheim I, Minnerup L, Costell M, microRNA-132, -134, and -138: A microRNA troika Friauf E, Rust MB (2014) Profilin1 activity in rules in neuronal dendrites. Cell Mol Life Sci 71:3987- cerebellar granule neurons is required for radial 4005 migration in vivo. Cell Adh Migr, 2014 Dec 12 (Epub
ahead of print) Schratt G (2014) Neurobiology: A molecular knife to dice depression. Nature 516:7529 Pirone A, Kurt S, Zuccotti A, Rüttiger L, Pilz P, Brown D, Franz C, Schweizer M, Rust MB, Rübsamen R,
Friauf E, Knipper M, Engel J (2014) 23 is essential Research Group Professor M. Rust for normal structure and function of auditory nerve synapses and is a novel candidate for auditory processing disorders. J Neurosci 34(2): 434-445. Main fields of research Neuronal actin dynamics is crucial for a number of Önel SF, Rust MB, Jacob R, Renkawitz-Pohl R (2014) processes that are essential for brain development Tethering membrane fusion: Common and different and functionality and that ultimately control players in myoblasts and at the synapse. J behavior, e. g. neuronal migration and Neurogenet, 28(3-4): 302-315 differentiation, synaptogenesis, neurotransmitter release, or synaptic plasticity. However, only little is known about the actin-binding proteins and upstream regulatory mechanisms that control actin dynamics in neurons. By exploiting gene-targeted General information about the institute mice, we aim to identify novel regulators of neuronal actin dynamics and to comprehensively characterize Research funding 1.194.466,31 € their function in the brain.
Research projects Contact Details: Title Functional role of the actin-binding proteins Karl-von-Frisch-Str. 1, 35032 Marburg, CAP1 and CAP2 in the mammalian brain Tel.:++49 (0) 6421-28 65021 Principal investigator(s) M. Rust Director: Professor Dr. Gerhard Schratt Summary Recent studies revealed a role for the actin-binding proteins CAP1 and CAP2 in actin dynamics of non-neuronal cells. We found a broad expression for both proteins in the developing and mature mouse brain. By exploiting gene-targeted mice, we aim to characterize the function of CAP1 and CAP2 in the mouse brain, focusing on neuronal
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Institute of Physiology and Pathophysiology
Research Group Professor J. Daut N, Ottmann C (2013) A semisynthetic fusicoccane stabilizes a protein-protein interaction and enhances Main fields of research the expression of k(+) channels at the cell surface. 1. Intracellular traffic of potassium channels. We Chem Biol (4):583-93. are studying the sorting signals which direct potassium channels to specific intracellular Schiekel J, Lindner M, Hetzel A, Wemhöner K, compartments. The channels include two-pore- Renigunta V, Schlichthörl G, Decher N, Oliver D, Daut domain potassium channels (K2P-channels), inward J (2013) Inhibition of the potassium channel TASK-1 rectifier channels (Kir channels). in rat cardiac muscle by endothelin-1 is mediated by phospholipase C. Cardiovasc Res 97(1):97-105 2. Regulation of single-channel conductance and kinetics of K2P-channels. We are studying the Renigunta V, Fischer T, Zuzarte M, Kling S, Zou X, mechanisms by which biophysical properties of Siebert K, Limberg MM, Rinné S, Decher N, potassium channels are regulated. Schlichthörl G, Daut J (2014) Cooperative 3. Potassium channels in cardiac muscle cells. We endocytosis of the endosomal SNARE protein are studying the role of the two-pore-domain syntaxin-8 and the potassium channel TASK-1. Mol potassium channels (K2P) TASK-1 and TREK-1 in Biol Cell ;25(12): 1877-91 cardiac muscle cells and we investigate the mechanisms by which G-protein-coupled receptors Renigunta V, Zou X, Kling S, Schlichthörl G, Daut J modulate these ion channels. (2014) Breaking the silence: functional expression of the two-pore-domain potassium channel THIK-2. Pflugers Arch Eur J Physiol 466(9):1735-45 Research projects Title Intracellular traffic of potassium channels Rinné S, Renigunta V, Schlichthörl G, Zuzarte M, Principal investigator(s) J. Daut Bittner S, Meuth SG, Decher N, Daut J, Preisig-Müller Summary We are studying the mechanisms R (2014) A splice variant of the two-pore domain underlying the intracellular traffic of potassium potassium channel TREK-1 with only one pore channels (TASK-1, TASK-3, TREK-1, THIK-2, Kir2.1, domain reduces the surface expression of full-length Kir2.2). We investigate the following transport steps TREK-1 channels. Pflugers Arch Eur J Physiol 466(8):1559-70 detail: (1) The export from the ER. (2) The transport between ER and the cis-Golgi complex. (3) The Kilisch M, Lytovchenko O, Schwappach B, Renigunta transport from the Golgi complex to the surface V, Daut J The role of protein-protein interactions in membrane. (4) Endocytosis into the early endosome. the intracellular traffic of the potassium channels Funded by DFG, SFB 593, PA4, – German Research TASK-1 and TASK-3. Pflugers Arch Eur J Physiology (in Foundation, Collaborative Research Centre 593 press) Funding period 2010 – 2014 Bodnár M, Schlichthörl G, Daut J The potassium current carried by TREK-1 channels in rat cardiac Title The function and signal transduction of TASK-1 ventricular muscle. Pflugers Arch Eur J Physiology (in and TREK-1 channels in the cardiovascular system press) Principal investigator(s) J. Daut
Summary We are studying the contribution of the potassium channels TASK-1 and TREK-1 to the whole-cell currents and to the action potential in Research Group Professor N. Decher cardiomyocytes using electrophysiological and cell biological methods. Main fields of research Funded by DFG, FOR 1086 Project 7 – German Our group focuses on several aspects of ion channel Research Foundation, Research Unit Programme research. We study the molecular pharmacology and 1086 the structure and function of different channels. In Funding period 2010-2014 addition, to these experiments in heterologous expression systems, we study ion channels in native tissue including Patch Clamp experiments of native Most important publications cardiomyocytes and brain slices. Another focus is the Anders C, Higuchi Y, Koschinsky K, Bartel M, functional study of ion channel mutations causing Schumacher B, Thiel P, Nitta H, Preisig-Müller R, human arrhythmias. These studies analyze the Schlichthörl G, Renigunta V, Ohkanda J, Daut J, Kato disease causing mechanism of inherited arrhythmias.
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Our recent novel field of research analyzes how RNA Most important publications editing alters the function and pharmacology of ion Marzian S, Stansfeld PJ, Rapedius M, Rinné S, channels. Nematian-Ardestani E, Abbruzzese JL, Steinmeyer K, Sansom MSP, Sanguinetti MC, Baukrowitz T, Decher Research projects N (2013) Side pockets provide the basis for a new Title TASK channels in the heart and their mechanism of Kv channel-specific inhibition. Nat extracellular pore structure Chem Biol 9: 507-513 Principal investigator(s) N. Decher Summary In this project we analyzed native TASK-1 Limberg M, Zumhagen S, Netter MF, Coffey AJ, channels in the sino-atrial node, using the TASK-1 Grace A, Rogers J, Böckelmann D, Rinné S, knock-out mouse, HL-1 cells and novel TASK Stallmeyer B, ,§Decher N, §Schulze-Bahr E (2013) Non blockers. In addition, we have analyzed the dominant-negative KCNJ2 gene mutations leading to extracellular pore structure of the cardiac K2P Andersen-Tawil syndrome with an isolated cardiac channel TASK-1. The third focus of the project was phenotype. Basic Res Cardiol 108: 353. §Shared on the characterization of novel K2P channel senior authors mutations causing inherited forms of arrhythmias. Funded by DFG – German Research Foundation Dolga A, Netter MF, Perocchi F, Doti N, Meissner L, Funding period 2012 – 2015 Tobaben S, Grohm J, Zischka H, Plesnila N, Decher N, Culmsee C (2013) Mitochondrial small conductance Title The role of `side pockets´ for the inhibition of SK2 channels prevent glutamate-induced oxytosis Kv channels by polyunsatturated fatty acids and and mitochondrial dysfunction. J Biol Chem 88: potassium channel blockers 10792-10804 Principal investigator(s) N. Decher Summary Voltage-gated potassium channels (Kv Schiekel J, Lindner M, Hetzel A, Wemhöner K, channels) are novel drug targets for pharmaceuticals Renigunta V, Schlichthörl G, Decher N, Oliver D, Daut currently under development against many diseases. J (2013) Inhibition of the potassium channel TASK-1 Our studies are supposed to provide a major in rat cardiac muscle by endothelin-1 is mediated by contribution to the understanding of the molecular phospholipase C. Cardiovasc Res 97: 97-105 pharmacology of Kv1 channels and set the stage for the rational `drug design´ and the development of Streit AK, Matschke LA, Dolga AM, Rinné S, Decher drugs, acting via the newly discovered `side pockets´ N (2014). RNA Editing in the Central Cavity as a of the channels. Mechanism to Regulate Surface Expression of the Funded by DFG – German Research Foundation Voltage-Gated Potassium Channel Kv1.1. J Biol Chem Funding period 2014 – 2017 289: 26762-26771 Friedrich C, Rinné S, Zumhagen S, Kiper AK, Title Mutations in the Popeye domain containing Silbernagel N, Netter MF, Stallmeyer B, Schulze-Bahr protein 2 gene (Popdc2) as a cause of congenital AV- E, Decher N (2014) Gain-of-function mutation in block TASK-4 channels and severe cardiac conduction Principal investigator(s) S. Rinné disorder. EMBO Mol Med 6:937-951 Summary Popeye domain containing (Popdc) proteins interact with the ion channel TREK-1, a Renigunta V, Fischer T, Zuzarte M, Kling S, Zou X, member of the two-pore-domain potassium (K2P) Siebert K, Limberg M, Rinné S, Decher N, channel family, playing a role in setting the resting Schlichthörl G, Daut, J. (2014) Co-operative membrane potential. Mice deficient for Popdc2 endocytosis of the endosomal SNARE protein developed a stress-induced sinus bradycardia. In our syntaxin-8 and the potassium channel TASK-1. Mol study we analyze a heterozygous Popdc2 mutation in Biol Cell 25: 1877-1891 a patient with severe atrioventricular block and reveal the disease-causing mechanism. Rinné S, Renigunta V, Schlichthörl G, Zuzarte M, Funded by UKGM – University Medical Centre Bittner S, Meuth SG, Decher N, Daut J, Preisig-Müller Giessen / Marburg R (2014) A splice variant of the two-pore domain Funding period 2014 – 2015 potassium channel TREK-1 with only one pore domain reduces the surface expression of full-length TREK-1 channels. Pflügers Archiv, 66: 1559-1570
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Research Group Professor D. Oliver Title Structure-based analysis of the molecular mechanisms of prestin-dependent cochlear Main fields of research amplification 1. Signaling by phosphoinositides and other Principal investigator(s) D. Oliver membrane lipids. Development of methods for live- Summary The exquisite acuity of mammalian cell imaging with fluorescence microscopy and for hearing relies on active mechanical amplification and acute manipulation of phosphopoinositide requires a process termed electromotility, i. e. concentrations by rapidly controllable enzymes. voltage-driven ultrafast length changes of sensory 2. Biophysics, molecular physiology and cellular outer hair cells (OHC). The elementary motor that regulation of ion channels, in particular potassium generates motility is prestin (SLC26A5), an anion channels (Kv, KCNQ, K2P, Kir). transporter-related, OHC-specific membrane 3. Physiology and pathophysiology of cochlear protein. So far, analysis of the molecular auditory hair cells and signal encoding by the mechanisms behind prestin’s function has been peripheral auditory system. hampered by a general lack of structural information 4. Structure and molecular function of the about SLC26 transporters. By homology modeling we membrane motor protein of outer hair cells, prestin have now developed a structural model of prestin (SLC26A5) and related anion transporters that is in excellent agreement with previous biophysical findings. We propose to validate and Research projects refine this structure and to use it as a template for Title Compartment-specific phosphoinositide elucidating the fundamental molecular features of dynamics in a central neuron prestin and related transporters. Principal investigator(s) D. Oliver Funded by DFG, SPP 1608 – German Research Summary Phosphoinositides (PIs) control many Foundation, Priority Programme cellular processes including synaptic function and ion Funding period 2012 – 2015 channel activity. We use hippocampal pyramidal neurons as a model to investigate Title Entwicklung einer Methodik zur automatisieten compartmentation of PI signaling. Changes in Untersuchung der Aktivität des Tumorsuppressors TEN in lebenden Zellen phosphatidylinositol (4,5)bisphosphate (PIP2) and phosphatidylinositol-(3,4,5)trisphosphate levels in Principal investigator(s) C. Halaszovich response to a variety of physiological stimuli will be Summary The tumor suppressor PTEN antagonizes examined using FRET imaging. Particular attention is the PI3K/Akt-pathway via its PI(3,4,5)P3/PI(3,4)P2-3- paid to the highly compartmentalized dendritic phosphatase activity. Recently, we were able to compartments and postsynaptic spines. develop a PTEN-chimera (PTENCiV) that is controlled Funded by DFG, SFB593, TP A12 – German Research by membrane voltage. In this study we will develop Foundation, Collaborative Research Centre 593 methods that will allow the activation of this Funding period 2011 – 2014 chimeric enzyme and the detection of its activity in living cells in a way that is amenable to automation. Title The mechanisms underlying receptor-mediated Funded by UKGM – University Medical Centre regulation of TASK and TREK channels Giessen / Marburg Principal investigator(s) D. Oliver Funding period 2011 – 2013 Summary TASK- und TREK channels are leak potassium Title Interaction of KCNQ and Erg potassium channels that are constitutively active at the resting channels in auditory hair cells potential, but are inhibited by a multitude of Principal investigator(s) M. Leitner metabotropic neurotransmitter and hormone Summary The sensitivity of mammalian hearing depends on cochlear amplification that is facilitated receptors. As these channels determine membrane + potential and electrical signaling in many neurons by the outer hair cell current IK,n. KCNQ4 K channels and non-excitable cells, their inhibition results in have been identified as molecular components, but depolarization and changes in excitability. Both cannot account for all properties of native currents. channel types are inhibited by receptors that couple We identified Erg channel subunits as potential via heterotrimeric G-proteins of the Gq/11 class. In interaction partners of KCNQ4. Hypothesizing that this project, we aim at elucidating the mechanisms heteromeric channels composed of KCNQ4 and Erg and molecular components of this Gq-dependent subunits determine the properties of the native signalling cascade that control TASK and TREK current, we analyze this interaction in outer hair cells channels. and heterologous expression systems. Funded by DFG, FOR 1086, TP 9; OL 240/3-1 – Funded by UKGM – University Medical Centre German Research Foundation, Research Unit Giessen / Marburg Programme 1086 Funding period 2014 – 2015 Funding period 2011 – 2014
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Title Homoclinic Bifurcations at Tonic-to-Bursting Title Bidirectional communication between non- Transitions: Underlying Mechanisms and Impact on neuronal acetylcholine and neuronal noradrenaline neuronal Synchronization in the spleen Principal investigator(s) U. Feudel (University of Principal investigator(s) A. del Rey Oldenburg) & H. A. Braun Summary The main question addressed here is Summary Analyzing the bifurcation structure of a whether interactions between non-neuronal, neuronal computer model which can reproduce lymphocyte-derived acetylcholine and noradrenaline physiologically and pathophysiologically most from sympathetic nerves in lymphoid organs can relevant impulse pattern, among them transitions affect the immune response. We focused on the from single-spike activity (tonic firing) to grouped spleen because this organ is not parasympathetically discharges which are often accompanied by innervated in rodents. The results obtained alterations of the neuronal synchronization state, for emphasize the need to consider the balance example, at wake-sleep transitions or during the between the effects of these mediators for the final development of epileptic seizures. immunoregulatory outcome. Funded by UKGM – University Medical Centre Funded by LOEWE (NNCS 56200076) Giessen / Marburg Funding period 2012 – 2014 Funding period 2010 – 2013 Title Counteracting the disruption of brain-immune system-joint communication: targeting the brain in Research group Professor A. del Rey arthritis Principal investigator(s) A. del Rey - in collaboration Main fields of research with Prof. Dr. R. Straub, Dept. of Internal Medicine I, Our research deals with interactions between the University Hospital Regensburg, Germany nervous, endocrine and immune systems under Summary We have recently shown that the physiological and pathological conditions. During this communication between the brain, the immune period, we focused on six closely related aspects of system, and the inflammatory, autoimmune process these interactions:1) the resetting of glucose that occurs in the affected joints during arthritis is homeostasis by brain-borne IL-1β; 2) bidirectional disrupted. During this period, we concentrated on influences between non-neuronal acetylcholine and studying the role that endogenous levels of neuronal noradrenaline in lymphoid organs, 3) the glucocorticoids play in the susceptibility to develop contribution of glucocorticoids in the sensitivity to arthritis in genetically resistant animals. develop arthritis and to induce regulatory T cell Funded by DFG – German Science Foundation (RE apoptosis; 4) brain neurotransmitter and cytokines 1451/4-2) levels in a model of neurodevelopmental disorders; Funding period 2009 – 2015 5) the role of the sympathetic nervous system in a parasitic infection model; 6) neuro-endocrine Title Immune-neuro-endocrine interactions during disturbances in patients with tuberculosis infections with parasites Principal investigator(s) A. del Rey - in collaboration Research projects with Dr. E. Roggero, Open Interamerican University (UAI), Rosario, Argentina Title Neuro-endocrine mechanisms of Interleukin- Summary We have shown that interference with the 1β-mediated resetting of glucose homeostasis functioning of the hypothalamus-pituitary-adrenal Principal investigator(s) A. del Rey axis aggravates the disease in animals infected with Summary We have shown that IL-1β induces a Trypanosoma cruzi, the parasite that causes Chagas’ prolonged and profound insulin-independent disease in humans. During this period, we focused hypoglycemia without eliciting neurological on the activity of the sympathetic nervous system in symptoms, and mediated by peripheral and central infected mice, and studied its contribution to the effects of the cytokine. During this period, we development of the disease. concentrated on the molecular mechanisms by Funded by Open Interamerican University, Argentina which brain-borne IL-1β might resets glucose Funding period 2012 – 2015 homeostasis by acting in the brain. Part of this work is included in the Doctoral Thesis of M. Title Endocrine responses during human tuberculosis Verdenhalven. Principal investigator(s) A. del Rey - in collaboration Funded by DFG – German Science Foundation (RE with Dr. O. Bottasso, Institute of Physiology, Medical 1451/3-1) Faculty, Rosario, Argentina Funding period 2009 – 2013 Summary We have shown that patients with
pulmonary tuberculosis have imbalanced endocrine and immune responses, associated with metabolic
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Preclinical Institutions alterations. During this period, we have: 1) Funded by DFG (SFB 593, TP A16) – German continued the follow-up of patients with Research Foundation, Collaborative Research Centre tuberculosis undergoing standarized long-term 593 theraphy, 2) identified TGFβ as the most likely Funding period 2012 – 2014 immune mediator that inhibits dehidro- epiandrosterone (DHEA) secretion, one of the most Title Regulation of TRPM3 in nociceptor neurons by marked alterations observed in patients with opioids tuberculosis. Principal investigator(s) J. Oberwinkler, S. Dembla & Funded by Argentinian Research Council M. Behrendt Funding period 2010 – 2014 Summary TRPM3 channels are expressed in nociceptor neurons, where these channels Research group Professor J. Oberwinkler participate in the detection of noxious heat and in inflammatory responses. We found that the Main fields of research activation of mu-opioid receptors, targets of the The group of Johannes Oberwinkler continued its most powerful analgesic drugs, leads to a strong long standing research focus on the functional inhibition of TRPM3 channels. We investigate the characterization of TRPM3 and TRPM1 channels, by intracellular signaling pathways and the functional investigating the biophysical and pharmacological consequences of this clinically important regulatory properties of these channels. Additionally, the mechanism. regulation of activity by intracellular signaling Funded by UKGM – University Medical Centre cascades of these channels was investigated. These Giessen / Marburg channels are highly interesting, because they have Funding period 2012 – 2014 been implicated in a number of physiological and pathophysiological processes with important Title Regulation of TRPM1 by G-protein-coupled implications for common human diseases (TRPM3: receptors and their signaling pathways insulin secretion, temperature and pain sensation; Principal investigator(s) J. Oberwinkler, M. Behrendt TRPM1: night blindness). & F. Schneider Summary Loss of function mutations of TRPM1 Research projects proteins (which are closely related to TRPM3 proteins) lead to nightblindness in humans and Title Regulation of TRPM3 activity by noradrenaline animal models. We study the functional properties in pancreatic beta cells of ion channels formed from TRPM1 proteins with Principal investigator(s) J. Oberwinkler, F. Mohr & respect to their pharmacology, biophysical M. Behrendt properties and their regulation by intracellular Summary TRPM3 channels are endogenously signaling cascades. expressed in pancreatic beta cells, where they form Funded by DFG (SFB 593, TP A16) – German ionotropic steroid receptors. Activation of these Research Foundation, Collaborative Research Centre channels leads to Ca2+ influx and subsequent 593 increase of glucose-evoked insulin release. However, Funding period 2012 – 2014 it is still unclear how TRPM3 activity is regulated in vivo. We found that noradrenaline suppresses Title Structure-affinity relationship of TRPM3 TRPM3 activity by activating alpha2-adrenoreceptors channels with their agonists and antagonists and subsequently releasing beta/gamma-subunits Principal investigator(s) J. Oberwinkler, M. Behrendt from Galphai-proteins. & C. Goecke Funded by DFG (SFB 593, TP A16) – German SummaryTRPM3 channels are potential therapeutic Research Foundation, Collaborative Research Centre targets for diverse diseases such as diabetes and 593 inflammatory pain. It is therefore important to Funding period 2009 – 2014 better understand how agonists and antagonists
interact with TRPM3 proteins. We study point Title Regulation of TRPM3 activity by inositide mutations of TRPM3 channels and systematically phospholipids modified small molecules in order to establish Principal investigator(s) J. Oberwinkler, M. Konrad, structure-activity relations with the aim of B. Nickl & F. Mohr developing channel modulators with improved Summary Many TRP channels, are regulated by selectivity and usefulness. phospholipids, most prominently by PIP2. In order to Funded by DFG (SFB 593, TP A16) – German investigate whether also TRPM3 channels are Research Foundation, Collaborative Research Centre regulated by PIP2, various enzymatic and 593 pharmacological approaches are used in order to Funding period 2012 – 2014 manipulate PIP2 and PIP3 levels in a controlled and precise way.
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Most important publications Deng W, Nies F, Feuer A, Bocina I, Oliver D, Jiang D (2013) Anion translocation through an Slc26 General information about the institute transporter mediates lumen expansion during tubulogenesis. Proc Natl Acad Sci USA 110:14972- Research funding 1.693.568,14 € 14977
Schiekel J, Lindner M, Hetzel A, Wemhoner K, Contact Details: Deutschhausstr. 2, 35037 Marburg, Renigunta V, Schlichthorl G, Decher N, Oliver D, Phone:++49 (0) 6421-28 66444 Daut J (2013) The inhibition of the potassium Director: Professor Dr. Dominik Oliver channel TASK-1 in rat cardiac muscle by endothelin-1 is mediated by phospholipase C. Cardiovasc Res
97:97-105
Straub I, Mohr F, Stab J, Konrad M, Philipp SE,
Oberwinkler J, Schaefer M (2013) Citrus fruit and fabacea secondary metabolites potently and selectively block TRPM3. Br J Pharmacol 168(8):1835-50 del Rey A, Balschun D, Wetzel W, Randolf A, Besedovksy HO (2013) A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNF operates during long-term potentiation and learning. Brain Behav Immun 33:15-23
Wirth T, Westendorf AM, Bloemker D, Wildmann J, Engler H, Mollerus S, Wadwa M, Schäfer MK, Schedlowski M, del Rey A (2014) The sympathetic nervous system modulates CD4(+)Foxp3(+) regulatory T cells via noradrenaline-dependent apoptosis in a murine model of lymphoproliferative disease. Brain Behav Immun 38:100-10
Wilke BU, Lindner M, Greifenberg L, Albus A, Kronimus Y, Bünemann M, Leitner MG, Oliver D (2014) Diacylglycerol mediates regulation of TASK potassium channels by Gq-coupled receptors. Nat Commun 5:5540
Gorbunov D, Sturlese M, Nies F, Kluge M, Bellanda M, Battistutta R, Oliver D (2014) Molecular architecture and the structural basis for anion interaction in prestin and SLC26 transporters. Nat Commun 5:3622
Drews A, Mohr F, Rizun O, Wagner TF, Dembla S, Rudolph S, Lambert S, Konrad M, Philipp SE, Behrendt M, Marchais-Oberwinkler S, Covey DF, Oberwinkler J (2014) Structural requirements of steroidal agonists of transient receptor potential melastatin 3 (TRPM3) cation channels. Br J Pharmacol 171(4):1019-32
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Department of Medical Psychology
Research Group Professor K. Thieme combined with operant pain therapy, 100% of chronic pain patients achieved pain relief for 6 and Main fields of research 82% for 12 months. Our studies are experimental, interventional, Funded by DFG Th 899-7/1 – German Research translational science projects to investigate Research Foundation, NIH – National Institute of anatomical mechanisms - baroreflex and nucleus Health & UKGM – University Medical Centre Giessen tractus solitarius (NTS) reflex arcs in chronic pain to / Marburg define and to influence the disturbed pain inhibition Funding period 2009 – 2015 mechanism. A new medical device and treatment method (SET) was developed and used for patients Title Evaluation of the “Assertiveness Training for as well as a RCT study with 60 fibromyalgia patients Medical Students” who got the SET was executed to proof the therapy Principal investigator(s) K. Thieme effects of pain freedom (Fig. 1). Summary An interventional study with 1150 medical students was performed in order to improve their communication and empathy skills by using my manual “Self-assertiveness training for medical students”. The interventional study investigates changes of anxiety, depression, empathy, sociopathy and training satisfaction as well as behavioral changes after the “Assertiveness training for medical students” in 1150 students of the 3rd semester. Standardized questionnaires and video-recorded behavioral observations of a role-play with an actor- patient were used to differ between 3 subgroups: empathy (36.85%), sociopathy (38.50%) and anxiety- depression (28.65%, Figure2). Figure 1 Changes of Clinical Pain immediately and 6-12 months after Systolic extinction training (SET) and Placebo Condition (PC)
Research projects Title Mechanism of Baroreflexsensitivity in Fibromyalgia Principal investigator(s) K. Thieme Funded by UKGM – University Medical Centre Giessen/ Marburg Funding period 2012 – 2014 Figure 2 Subgroups in medical students (N = 767): Title Development of two computer supported Subgroup1: Empathy group (cluster1 36.85%), subgroup2: instruments for screening and assessment of Fear Soziopathy (cluster2, 38.50%), subgroup3: Anxiety- Avoidance Beliefs in patients with low back pain Depression-Group (cluster3. 24.65%) older than 65 years (eAMICA-K and eAMIKA) Funded by Teaching Research Fond Principal investigator(s) S. Quint Funding period 2012 – 2015 Funded by Kempkes Foundation
Funding period 2012 – 2014 Title Stress and sensitization in medical students
before the anatomy exam Title Mechanism of baroreflexsensitivity (BRS) – Principal investigator(s) K. Thieme pathophysiology and treatment Summary The multicenter study (UNC, ETH-Zürich) Principal investigator(s) K. Thieme investigates the relationship between stress Summary We developed a novel medical device and (anatomy-exam) and sensitization measured as treatment method to increase the diminished BRS in vibrotactile discrimination capacity in 70 healthy chronic pain patients. Baroreceptors transmit individuals assuming a positive correlation because pressure information to the nucleus tractus of GABAerg inhibition. Sensory thresholds in solitaries, which inhibits pain, blood pressure, sleep discrimination tasks, skin conductance level, cortisol disturbances, anxiety, and hyperglycemia. When
Research Report 2013 of the Medical Faculty of the Philipps University Marburg - Reference period 2011-2012 31 Preclinical Institutions saliva and subjective ratings of stress and anxiety Meller T, Thieme K. Pain inhibition after systolic were recorded immediately before the oral anatomy extinction training. [Schmerzhemmung nach exam controlled by a baseline situation. systolischer Extinktionstherapie (SET) bei Funded by CNS Therapy AG Fibromyalgie.] Meeting of the German Association Funding period 2013 – 2015 for Study of Pain, Hamburg, Oktober 2014
Note This research report does not include the not- Thieme K, Kraemer H, Koehler U, Meller T, Maixner funded projects such as “Characteristics of sleep W, Gracely, RH. Psychological Pain Treatment in pattern in fibromyalgia and their changes after Fibromyalgia: Systolic Extinction Training (SET) systolic extinction training”, “Immunological changes Restores Baroreflex Sensitivity, Reduces Pain in patiens suffering from rheumatoid arthritis Sensitivity and Clinical Pain Report. 15th World episode after systolic extinction training” as well as Congress of the International Association for Study “Changes of sympathetic activity of fibromyalgia of Pain (IASP), Buenos Aires, Argentina, 2014 tested in LBNP after systolic extinction training – A microneurography study.” Thieme K, Maixner W, Gracely RH. Cardiac Gating of Peripheral Afferent Stimulation Restores Baroreflex Sensitivity, Reduces Pain Sensitivity and Clinical Pain th Report in Fibromyalgia Patients. 15 World Congress General information about the institute of the International Association for Study of Pain (IASP), Buenos Aires, Argentina, 2014 Research funding 33.146,05 € Zeiler AL, Koehler W, Kesper K, Cassel W, Thieme K.
Schlafmuster bei Fibromyalgie vor und nach
systolischem Extinktionstraining (SET). Somnologie Most important publications 2014, 18(1): R56 22nd Meeting of German Thieme K, Turk DC, Gracely RH, Maixner W, Flor H. Association for Sleep Research and Sleep Medicine The relationship among psychological and psychophysiological characteristics of fibromyalgia Book chapter patients. J Pain. doi: 10.1016/j.jpain.2014.11.009. Finset A, Thieme K. (2014). Psychosocial Approaches Epub 2014 Nov 26. in Rheumatic Diseases. In: Weller J (Ed.) EULAR
Textbook on Rheumatic Diseases - Online Course. ). Posterabstracts (per-reviewed) Medwellmedia; Chapter 6, pp: 1 – 26 Flor H, Thieme K, Kleinböhl D, Kießling U, Wang H,
Schiltenwolf M, Konrad Ch, Schmelz M. Enhancing Thieme K. Fibromyalgie. In: Petermann F & Vaitl D extinction training by cannabis: A randomized (Hrsg.) Entspannungsverfahren. Das Praxishandbuch. controlled trial in patients with chronic 5. Auflage 2014, Beltz Verlag, Weinheim, Basel; S. musculoskeletal pain. 15th World Congress of the 266 – 278 International Association for Study of Pain (IASP),
Buenos Aires, Argentina, 2014 Patents
2013 Lautenschlaeger G, Meller T, Malinowski R, Wilhelm Thieme K, Maixner W, Gracely RH. OLG 150/4 Prov K, Birklein F, Kaps M, Thieme K, Kraemer H. Thieme K, Maixner W, Gracely RH. OLG 150/4 Prov-2 Sympathetic activity in patients with fibromyalgia – a microneurographic study. [Sympathische Nerven- Since it is a Translational Science Project, this study aktivität bei Fibromyalgie Patienten – eine belongs to the most important research projects. It is Mikroneurographiestudie]. Meeting of the German a multicenter study and was supported by DFG (Th Association for Study of Pain, Hamburg, Oktober 899/7-1: “Pathways of chronic pain”) and the NIH 2014) (R01AR054895-01A1: “Mechanisms of sensory
Processing in Fibromyalgia”) as well as the UKGM. It Meller T, Wolf S, Malinowski R, Maixner W, Gracely started in 2009 at the Center for Neurosensory RH, Thieme K. Psychological pain treatment in Disorders, University of North Carolina (UNC), fibromyalgia: Systolic extinction training (SET) and Chapel Hill, USA (director: Dr. William Maixner, PhD, cardiovascular training restores baroreflex DDS) and continued through 2011 as a collaboration sensitivity, reduces pain sensitivity and clinical pain between UNC (Dr. William Maixner, PhD, DDS), the report. 15th World Congress of the International Philipps University Marburg respective the Association for Study of Pain (IASP), Buenos Aires, Department of Medical Psychology (Director: Dr. Kati Argentina, 2014 Thieme, PhD) and the CNS Therapy, AG, Switzerland
(Director: Dr. Marc Mathys, PhD).
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An important result of the study was the development of a new medical device - the systole- electrostimulator-synchronizer. The device treats pain and other chronic diseases. It allows the delivery of individual adjusted electrical stimuli dependent on cardiac cycle through the fingers. The cardiac gated electrical pulses stimulate the NTS reflex arcs, through the baro receptors and results in the long-term extinction of pain when the stimulation is combined with psychological pain therapy.
The new device was accepted by the Office of Technology and Discoveries (OTD) at the University of North Carolina (UNC), Chapel Hill, in 2011 for a submission of 2 provisional patents that the OTD supported in 2013 These provisional patents were then converted into the submission of a final patent in 2014.
The UNC has supported the submission of the provisional patents, only under the condition that I could find a sponsor who will commercialize the technology. Additionally to the costs of the patent submissions, UNC miniaturized the device at their own expense. After a 2 years search, the company ‘CNS Therapy AG’ (Director: Phd. Marc Mathys and investors to sponsor the technology. Currently the sponsor is finding medtech companies in Germany and US that to prepare CE-certification and FDA.
UNC and CNS Therapy AG submitted final patent in 2014. Recently we have received a positive feedback to the patent filing by the American patent office. CNS Therapy, AG supported the RCT study at the University Marburg. Public and private investments together in the project exceed US$ 3,000,000.
Until the submission of the final patent in March 2014, we were not allowed to submit or publish any research results in any papers or books.
2014 Thieme K, Maixner W, Monbureau O, Gracely RH. OTD 12-0059 PCT/US14/26579
Contact Details: Karl-von-Frisch-Str. 4, 35032 Marburg Phone:++49 (0) 6421-28 66250 Director: Professor Dr. Kati Thieme
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Institute of Medical Sociology and Social Medicine
Research Group Professor U. Mueller
Main fields of research Medical Demography General information about the institute Epidemiology Health Care Research Research funding 62.789,45 €
Research projects Most important publications Title Computer-based Diabetes Risk-Management Reese JP, Wienemann G, John A, Linnemann A, System (CDRM) Balzer-Geldsetzer M, Mueller UO, Eienbröker C, Principal investigator(s) U. Mueller Tackenberg B, Dodel R (2014) Preference-based Summary The main purpose of the study yields on a Health status in a German outpatient cohort with science-based validation of the integrated health multiple sclerosis. Health Qual Life Outcomes. 11:162 service model and the effectiveness of the computer-based risk-management-tools tested Mazur A, Westerman R, Werdecker A, Mueller U within a clinical study. The research project is (2014): Testosterone and type 2 diabetes in men. proposed to evaluate cooperation of technical Aging Male. 17(1):18-24 solutions according to methods of secondary prevention on a scientific background. The results Ng M, Fleming T, Robinson M, …, , Werdecker A, should provide the efficiency of the already Lopez AD, Murray CJ, Gakidou E (2014) Global, implemented disease management programs. regional, and national prevalence of overweight and Funded by ICW - InterComponentWare AG, Roche obesity in children and adults during 1980-2013: a Diagnostics Deutschland GmbH systematic analysis for the Global Burden of Disease Funding period 2007 – Study 2013. Lancet. 384(9945):766-81
Title Competence Center Mortality-Follow-Up of the Kassebaum NJ, Bertozzi-Villa A, Coggeshall MS,…, German National Cohort Mueller UO,… ,Westerman R,…, , Naghavi M, Murray CJ, Lozano R (2014) Global, regional, and national Principal investigator(s) U. Mueller levels and causes of maternal mortality during 1990- Summary The German National Cohort as an 2013: a systematic analysis for the Global Burden of interdisciplinary research consortium includes Disease Study 2013. Lancet. 384(9947):980-1004 scientists of the Hemholtz and Leibniz-community, universities and other research departments. Wang H, Liddell CA, Coates MM, Mueller UO, … , The major aim of the study is to search for causes Westerman R, …, Vos T, Lopez AD, Murray CJ (2014) and risk factors for the development of the most Global, regional, and national levels of neonatal, important chronic diseases, especially cardiovascular infant, and under-5 mortality during 1990-2013: a diseases, cancer, diabetis mellitus, neuro- systematic analysis for the Global Burden of Disease degenerative and mental diseases, illness of the Study 2013. Lancet. 384(9947):957-79 musculoskeletal system, respiratory tracts, infectious diseases and their grades in pre-clinical development Murray CJ, Ortblad KF, Guinovart C, … , Westerman and health related restraint over the life course. The R, …, Zou XN, Lopez AD, Vos T (2014) Global, study is based on a random sample of the total regional, and national incidence and mortality for population in 18 study centers spread all over HIV, tuberculosis, and malaria during 1990-2013: a Germany, including 200.000 probands (100.000 systematic analysis for the Global Burden of Disease female/ 100.000 male) aged between 20 and 69 Study 2013. Lancet. 384(9947):1005-70 years. Funded by BMBF – Federal Ministry of Education Naghavi M, Wang H, Lozano R, …, Mueller U, …, and Research, Hemholtz u. Leibniz-Gemeinschaft Westerman R, …, Werdecker A, …, Vos T, Lopez AD, Funding period 2014 – 2018 Murray CJ (2014) Global, regional, and national age sex specific all-cause and cause-specific mortality for
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240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. Dec 17. pii: S0140-6736(14)61682-2. [Epub ahead of print]
Contact Details: Karl-von-Frisch-Str. 4, 35043 Marburg, Phone:++49 (0) 6421-28 66244 Director: Professor Dr. Ulrich Mueller
Research Report 2015 of the Medical Faculty of the Philipps University Marburg - Reference period 2013-2014 35 Clinical-theoretical Institutions
Institute of General and Family Medicine, Preventive and Rehabilitative
Research Groups
Professor E. Baum, Professor A. Becker and Professor N. Donner-Banzhoff
Main fields of research Cardiovascular Health: Diagnosis, Chronic Care, Prevention; Chronic Pain: Etiology, Treatment Strategies, Primary and Secondary Prevention; Clinical Decision Making: Cognitive Processes, Clinical Prediction Rules, Validity of the History and Physical Signs; Decision Support Technologies; Intercultural Primary Care; Professional Learning and Behavioural Change; Medical Care in rual regions.
Research projects Title Transition from localized low back pain to Title Diagnosis in primary care practice: cognitive chronic widespread pain in general practice: strategies Identification of risk factors, preventive factors, and Principal investigator(s) N. Donner-Banzhoff key elements for treatment Summary General Practitioners (GPs) are the most Principal investigator(s) A. Becker important point of entry into the health care system. Summary The aim of the study is to identify They have to differentiate between frequently predictors of pain generalization in consulters for encountered benign problems and potentially LBP in general practice and to identify individual serious conditions presented by their patients. resources for the prevention of the transition from Within this project, the cognitive strategies GPs use chronic localized LBP to chronic widespread pain for their diagnostic assessment will be investigated (CWP). These results provide the psychological in collaboration with the MPI for Human background information on CWP patients which can Development, Berlin. 300 consultations in 12 be used for an intervention addressing resources practices were videotaped and are being analysed. and risk factors of this patient group. This Funded by DFG – German Research Foundation intervention will be implemented and tested on Funding period 2011 – 2013 clinical efficacy in the second phase of this research project. In summary this project aims at three main Title Center of Competence for General research objectives Practitioners’ vocational training in the state of Funded by BMBF – Federal Ministry of Education Hessen (middle and northern part) and Research Principal investigator(s) E. Baum Funding period 2011 – 2014 Summary Vocational training for general practitioners/family physicians (GPs) is often Title Developing and evaluation of a physical- disrupted and uncoordinated. Germany is facing an activating therapy for low back pain in the elderly increasing lack of young GPs. This programme helps (graded activity & graded exposure principles) – to overcome barriers by initiating cooperations for STÄP [Schmerztherapie Ältere Patienten] the full time of vocational training and offers Principal investigator(s) A. Becker & S. Quint seminars, mentoring and evaluates each step. This is Summary There is a lack of evidence-based therapy performed in close cooperation with the principles for low back pain in the elderly in primary Competence Center in south Hessen and the other care. This is a pre-study for an interventional project: players in the system. Physiotherapy-manuals for two activating Funded by Social Ministry Hessen therapeutic approaches in older back pain patients Funding period 2013 – 2014 are developed in cooperation with known experts. Pre-testing of the will be performed in a feasibility Title Title arriba-PRO study. Principal investigator(s) N. Donner-Banzhoff Funded by DFG – German Research Foundation Summary The decision-support software “arriba” Funding period 2011 –2013 which has been developed within our department, is
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Clinical-theoretical Institutions being systematically implemented in Baden- Bias in CME-Journals Württemberg as part of a primary care gatekeeping Psychiatric treatment of immigrants from scheme (Hausarztzentrierte Versorgung der AOK). Turkey Patients counseled by their General Practitioners Prescribing of thyroid hormones in primary care using the software, form a virtual cohort. By Development and psychometric testing of a assessing future cardiovascular events, we will be standardised instrument to assess the quality able to adjust the predictive algorithm underlying of vocational training the prognosis provided by arriba. Patient information leaflets dissemated in Funded by GPZK primary care practice Funding period 2011 – 2014 Epidemiology of low back pain and coping strategies in elderly patients Title OptRisk: Optimisation of risk consultancy Geographical distribution of obesity through presentation of changeability of individual Effectiveness of computer-based counselling life expectancy for chronic low back-pain patients Principal investigator(s) N. Donner-Banzhoff Implementation of a guideline about chest pain Summary The aim of this project is to improve the in primary care presentation of risks in a decision aid for Diagnosis of headache in Primary Care cardiovascular diseases. Central to the research Diagnosis of leg edema in Primary Care project is the comparison of the presentation on the Chronic skin disease in Primary Care basis of 1) the absolute risk employed so far (10-year Teaching points and feedback during the prognosis), and 2) the event-free lifetime. Main mandatory general practice elective – an question: Which presentations of prognosis and ethnographic study therapeutic effects are particularly suitable in patient consulting – absolute risk or lifetime? Funded by BMBF – Federal Ministry of Education and Research Funding period 2011 – 2014 General information about the institute
Title Community nurse in Muschenheim Research funding 893.138,75 € Principal investigator(s) E. Baum & D. Kuhn Summary Declining numbers of General Practitioners (GPs) in Germany and especially in rural regions lead to under-supply of the ageing Most important publications population in these regions with respect to basic Bösner S, Bönisch K, Haasenritter J, Schlegel P, medical needs. This local and privately funded Hüllermeier E and Donner-Banzhoff N (2013) Chest initiative introduces consulting hours and home pain in primary care: is the localization of pain visits run by community nurses living in the village diagnostically helpful in the critical evaluation of and special offers like medication check and patients? - A cross sectional study. BMC Family gymnastics for elderly people. The project is Practice 14:154 evaluated by qualitative and quantitative methods. Funded by Private local sponsor Sauerborn, silver Bösner S, Hartel S, Diederich J, Baum E (2014) star prize Diagnosing headache in primary care: a qualitative Funding period 2013 – 2014 study of GPs' approaches. Br J Gen Pract 64:e532-7
Minor Project without External Funding 2014 Diederich J, Hartel S, Baum E, Bösner S (2014) Bias-calculator Strategies for diagnosing leg oedema in primary care: A qualitative study of GPs' approaches. Eur J Systematic reviews of symptom evaluating Gen Pract 17:1-7 studies in primary care
Qualitative studies about use of allopurinol, Viniol A, Keunecke C, Biroga T, Stadje R, Dornieden dermatological problems, leg edema und K, Bösner S, Donner-Banzhoff N, Haasenritter J, headache in primary care Becker A (2014) Studies of the symptom abdominal Evaluation of an OSCE about decision making in pain - a systematic review and meta-analysis. Fam undergraduate training Pract 31:517-29 Impact evaluation of the seminar ‘Differential
diagnosis in Primary Care’ Viniol A, Jegan N, Leonhardt C, Brugger M, Strauch K,
Barth J, Baum E, Becker A (2013) Differences Minor Projects without External Funding or between patients with chronic widespread pain and External Funding in Previous Years: local chronic low back pain in primary care - a
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Clinical-theoretical Institutions comparative cross-sectional analysis. BMC Musculoskelet Disord 14:351
Hirsch O, Strauch K, Held H, Redaelli M, Chenot JF, Leonhardt C, Keller S, Baum E, Pfingsten, M, Hildebrandt J, Basler HD, Kochen MM, Donner- Banzhoff N, Becker A (2014) Low back pain patient subgroups in primary care – pain characteristics, psychosocial determinants and health care utilization. Clin J Pain 30: 1023-32
Donner-Banzhoff N, Haasenritter J, Hüllermeier E, Viniol A, Bösner S, Becker A (2014) The comprehensive diagnostic study is suggested as a design to model the diagnostic process. J Clin Epidemiology 67:124 -132
Senge R, Bösner S, Dembczynski K, Haasenritter J, Hirsch O, Donner-Banzhoff N, Hüllermeier E (2014) Reliable classification: Learning classifiers that distinguish aleatoric and epistemic uncertainty. Information Sciences 255:16–29
Viniol A, Bösner S, Baum E, Donner-Banzhoff N (2013) Forgotten drugs: long-term prescriptions of thyroid hormones – a cross-sectional study. Int J Gen Medicine 6:329 – 334
Contact Details: Karl-von-Frisch-Str. 4, 35043 Marburg Tel.:++49 (0) 6421-28 65120 Director: Professor Dr. Erika Baum
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Institute of Medical Biometry and Epidemiology
Research Group Jun.-Prof. Dr. Nina Timmesfeld implementation of reliable validation and replication (provisional Director) strategies and gene-characterisation. Funded by BMBF, 01GS0830 – Federal Ministry of Main fields of research Education and Research Statistical methods for genetic-epidemiological Funded period 2008 – 2013 studies on complex diseases, particularly for genome-wide association analyses. Methodology of clinical studies, particularly adaptive statistical design methods and methods for data-dependent General information about the institute design changes. Research Funding 96.658,30 € Research projects Title Central biostatistical support, data and data quality management for the research association on Most important publications psychotherapy on eating disorders (Eating Disorders Berndt SI, Gustafsson S, Mägi R, Ganna A, Jarick I, …, Diagnostic and Treatment Network, EDNET), Speliotes EK, North KE, Loos RJ, Ingelsson E (2013) subproject TP9 Genome-wide meta-analysis identifies 11 new loci Principal investigator(s) N. Timmesfeld for anthropometric traits and provides insights into Summary IMBE/KKS provide a biostatistical and data genetic architecture. Nature Gen 45:(5): 501-512 management unit for the EDNET-network. Our tasks, depending on single subprojects, comprise central Dempfle A, Herpertz-Dahlmann B, Timmesfeld N, randomization, data management, statistical design, Schwarte R, Egberts K, Pfeiffer E, Fleischhaker C, monitoring and analysis, statistical supervision Wewetzer C, Bühren K (2013) Predictors of the Funded by BMBF, 01GV0623 – Federal Ministry of resumption of menses in adolescent anorexia Education and Research nervosa. BMC Psychiatry 13: 308- Funded period 2006 – 2013 Mylius V, Ayache SS, Ahdab R, Farhat WH, Zouari HG, Title R-package for optimal and flexible multistage Belke M, Brugières P, Wehrmann E, Krankow K, designs for genetic-epidemiological studies Timmesfeld N, Schmidt S, Oertel WH, Knake S, Principal investigator(s) H. Schäfer Lefaucheur JP (2013) Definition of DLPFC and M1 Summary During the last years we developed according to anatomical landmarks for navigated optimal multistage designs for genome-wide brain stimulation: Inter-rater reliability, accuracy, association studies allowing a stepwise reduction of and influence of gender and age. Neuroimage 78: a genotyped markerset on promising markers during 224-232 the course of a study. Also, we developed and enhanced the conditional rejection probability Nguyen TT, Schäfer H, Timmesfeld N (2013) Making principle. Aim of this project is the development of a Medical Decisions in Dependence of Genetic package for the statistical program system R Background: Estimation of the Utility of DNA Testing implementing these procedures in Clinical, Pharmaco-Epidemiological or Genetic Funded by BMBF, 01EZ0939 – Federal Ministry of Studies. Genetic Epidemiology 37:(4): 311-322 Education and Research Funded period 2010 – 2013 Herpertz-Dahlmann B, Schwarte R, Krei M, Egberts K, Warnke A, Wewetzer C, Pfeiffer E, Fleischhaker C, Title Molecular mechanisms on obesity – central Scherag A, Holtkamp K, Hagenah U, Bühren K, statistical genomics and data management, Konrad K, Schmidt U, Schade-Brittinger C, subproject TP15a Timmesfeld N, Dempfle A (2014) Day-patient Principal investigator(s) H. Schäfer treatment after short inpatient care versus Summary With this subproject we provide continued inpatient treatment in adolescents with biostatistical support for the genetic- anorexia nervosa (ANDI): a multicentre, randomised, epidemiologically orientated subprojects of the open-label, non-inferiority trial. The Lancet network. We provide genetic-statistical methods, 383:1222-1229 particularly for the analysis of genome-wide association studies and the development and Jarick I, Volckmar A-L, Pütter C, Pechlivanis S, Nguyen TT, Dauvermann MR, Beck S, Albayrak Ö,
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Scherag S, Gilsbach S, Cichon S, Hoffmann P, Degenhardt F, Nöthen MM, Schreiber S, Wichmann HE, Jöckel KH, Heinrich J, Tiesler CMT, Faraone SV, Walitza S, Sinzig J, Freitag C, Meyer J, Herpertz- Dahlmann B, Lehmkuhl G, Renner TJ, Warnke A, Romanos M, Lesch KP, Reif A, Schimmelmann BG, Hebebrand J, Scherag A, Hinney A (2014) Genome- wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention- deficit/hyperactivity disorder. Mol Psychiatry 19: 115-121
Knoll N, Jarick I, Volckmar A-L, Klingenspor M, Illig T, Grallert H, Gieger C, Wichmann HE, Peters A, Wiegand S, Biebermann H, Fischer-Posovszky P, Wabitsch M, Völzke H, Nauck M, Teumer A, Rosskopf D, Rimmbach C, Schreiber S, Jacobs G, Lieb W, Franke A, Hebebrand J, Hinney A. Mitochondrial DNA variants in obesity. PLoS ONE (2014) 9: (5): e94882-
Mehta C, Schäfer H, Daniel H, Irle S (2014) Biomarker driven population enrichment for adaptive oncology trials with time to event endpoints. Statistics in Medicine 33: 4515-4531
Contact Details: Bunsenstr. 3, 35037 Marburg Tel.:++49(0) 6421-28 66208 Director: Junior Professor Dr. Nina Timmesfeld
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Institute of Pharmacology and Toxicology
Professor R. Grosse, Professor F. Czubakyo in response to extracellular signaling cues. Notably, Professor T. Plant, Professor T. Worzfeld these actin structures differ in size and shape as well as in their temporal appearance and dynamics. Thus, a picture emerges that suggests that mammalian Main fields of research cells may have different pathways and mechanisms We aim at understanding some of the principal to assemble specific nuclear actin filaments for cellular mechanisms that control cell shape and distinct, yet mostly unknown functions. We motility. Our goal is to identify and characterize investigate how growth factor receptors can trigger relevant receptors and cytoskeletal signaling nuclear actin polymerization and how this impinges components that may represent novel molecular on the cancer cell phenotype. Some of these targets in particular for cancer and anti-invasive extracellular cues converge at the level of nuclear therapies. One focus of our institute is to study formin activity and subsequent regulation of signal regulations of actin dynamics through Rho- transcriptional events. GTPases and the formin family of actin nucleators and their interplay with nuclear actin dynamics and Calcium Signaling transcriptional events, which impinges on cancer cell Properties and regulation of TRPC and TRPV channel behavior such as proliferation and invasiveness. subunits Furthermore, current projects involve the analysis of The transient receptor potential (TRP) family of calcium homeostasis and of plexin receptor signaling channel subunits is a relatively new and functionally pathways to Rho proteins and the biological roles of diverse family of channel proteins with nearly 30 plexins under physiological and pathophysiological members in mammals. The subunits form cation conditions for the development of pharmacological channels, which are often Ca2+ permeable, and have agents, which target semaphorins and plexins. a diversity of physiological roles ranging from sensory transduction to cation transport across Cytoskeletal Signaling epithelia. Because of these roles, TRP channels are Dynamic rearrangement of the cytoskeleton putative pharmacological targets in a number of regulates responses to a variety of extracellular conditions. Our work focuses on the function, signals that allow cells to move or to change shape. properties and regulation of members of the TRPC Actin dynamics is controlled by defined signaling (canonical or classical) and TRPV (vanilloid) pathways, which orchestrate the activity of distinct subfamilies of TRP channels. We study channels in actin nucleation factors. The largest family of actin native tissues, particularly neurons of the central nucleators is represented by the formins, which are nervous system, and channels formed by TRP characterized by their highly conserved formin subunits or mutants thereof after expression in homology (FH) domain. Many diaphanous formins mammalian cells. are regulated through physical interactions with Rho family proteins, which can function as molecular Plexin Receptor Signaling switches to relay signal instructions to various Plexins comprise a family of transmembrane cellular responses. Interestingly, some formins such proteins which serve as receptors for semaphorins. as mDia1 and mDia2 govern transcriptional activity While they have initially been discovered as of the Serum Response Factor (SRF) through their important axon guidance molecules during neural effects on actin polymerization. One current major development, plexins are now recognized as key focus of our lab is to understand formin-induced regulators of intercellular communication in many nuclear actin assembly for nuclear dynamics, which different organ systems. The current projects of the may have implications for cancer cell behavior, lab focus on the analysis of plexin signaling pathways differentiation and nuclear architecture. For our and the biological role of plexins under physiological investigations we employ or develop methods for and pathophysiological conditions, particularly in 3D-collagen live cell assays, spatiotemporal cancer and during organ regeneration. optogenetic regulation of endogenous diaphanous or mDia formins as well as microscopy-based cytoskeletal analysis in living cells. Research projects Title The importance of formins for tumor Function of nuclear actin in cancer cells progression and metastasis in vivo Recent progress in the field of nuclear actin Principal investigator(s) R. Grosse dynamics has determined nuclear actin structures in Funded by DFG AI24/11-1 – German Research somatic cells either under steady state conditions or Foundation
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Clinical-theoretical Institutions
Funding period 2009 – 2013 Title Cdc42 signalling bei akutem Nierenversagen und Nierenfibrose Title Signal transduction of diaphanous formins in Principal investigator(s) T. Worzfeld tumor cell mobility and invasive cell migration Funded by UKGM – University Hospital Giessen / Principal investigator(s) R. Grosse Marburg Funded by DFG GR 2111/2-1– German Research Funding period 2014 – 2016 Foundation Funding period 2010-2013 Title Transmit-Einwerbung Principal investigator(s) A. Aigner Title Ras-dependent pathways in human cancer“ Funded by Industry 2013.149.1 Project A07: Die Rolle von CXorf22 in der Integrin- Funding period from 2009 on abhängigen Tumorinvasion Principal investigator(s) R. Grosse Title Die Bedeutung eines neu entdeckten Funded by DFG, TR 17 – German Research filamentösen Aktin-Netzwerks im Zellkern von Foundation, Transregional Collaborative Research Tumorzellen Centre 17 Principal investigator(s) R. Grosse & F. Czubayko Funding period 2011 – 2013 Funded by Wilhelm Sander Foundation Funding period 2014 – 2016 Title Mechanismus und Funktion von Plasma- membran Blebben und Freisetzung in Tumorzell- invasion Most important publications Principal investigator(s) R. Grosse Nürnberg A, Kollmannsperger A, Grosse R (2014) Funded by Deutsche Krebshilfe Pharmacological Inhibition of Actin Assembly to Funding period 2012 – 2014 Target Tumor Cell Motility. Rev Physiol Biochem Pharmacol 166:23-42 Title Mechanism of the Cellular Compartmentation and its relevance for Diseases – Project A14 Grosse R, Vartiainen MK (2013) To be or not to be Principal investigator(s) R. Grosse assembled: progressing into nuclear actin filaments. Funded by DFG, Collaborative Research Centre 593 – Nat Rev Mol Cell Biol 14(11):693-7 Funding period 2011 – 2014
Kreßner C, Nollau P, Grosse R, Brandt DT (2013) Title Rolle von Plexinen für die Pathogenese des Functional interaction of SCAI with the SWI/SNF kolorektalen Karzinoms complex for transcription and tumor cell invasion. Principal investigator(s) Grikscheit PLoS One 8(8):e69947 Funded by Kempkes Foundation
Funding period 2014 – 2015 Plant TD (2014) TRPs in mechanosensing and volume
regulation. Handb Exp Pharmacol 223:743-66. Title Die Bedeutung eines neu entdeckten Baarlink C, Wang H, Grosse R (2013) Nuclear actin dynamischen filamentösen Aktin-Netzwerks im network assembly by formins regulates the SRF Zellkern von Tumorzellen coactivator MAL. Science 340(6134):864-7 Principal investigator(s) R. Grosse & F. Czubayko
Funded by Sander Foundation, No. 2013.149.1 Worzfeld T*, Swiercz JM, Sentürk A, Genz B, Funding period 2014 – 2016 Korostylev A, Deng S, Xia J, Hoshino M, Epstein JA,
Chan AM, Vollmar B, Acker-Palmer A, Kuner R, Title Nuclear actin turnover in cancer Offermanns S (2014) Genetic dissection of plexin Principal investigator(s) D. Brandt signaling in vivo. Proc Natl Acad Sci USA 111:2194- Funded by UKGM – University Hospital Giessen and 2199, *corresponding author Marburg
Funding period 2014 – 2016 Adhikary T*, Brandt DT*, Kaddatz K, Stockert J,
Naruhn S, Meissner W, Finkernagel F, Obert J, Lieber Title In vivo Bedeutung des MAL/SRF Repressors S, Scharfe M, Jarek M, Toth PM, Scheer F, Diederich SCAI für die Tumormetastasierung WE, Reinartz S, Grosse R, Müller-Brüsselbach S, Principal investigator(s) R. Grosse Müller R (2013) Inverse PPARβ/δ agonists suppress Funded by DFG GR 2111/2-2 – German Research oncogenic signaling to the ANGPTL4 gene and inhibit Foundation cancer cell invasion. Oncogene 32(44):5241-52, Funding period 2014 – 2017 *shared first author
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Clinical-theoretical Institutions
Purvanov V, Holst M, Khan J, Baarlink C, Grosse R (2014) G-protein-coupled receptor signaling and polarized actin dynamics drive cell-in-cell invasion. Elife. 2014 20:3
Baarlink C, Grosse R (2014) Formin' actin in the nucleus. Nucleus 5(1):15-20
Bodmann EL, Rinne A, Brandt D, Lutz S, Wieland T, Grosse R, Bünemann M (2014) Dynamics of Gαq- protein-p63RhoGEF interaction and its regulation by RGS2. Biochem J 458(1):131-40 3.779 Worzfeld T, Offermanns S (2014) Semaphorins and plexins as therapeutic targets. Nat Rev Drug Discov 13(8):603-21
General information about the institute
Research funding 649.145,09 €
Contact Details: Karl-von-Frisch-Str. 1, 35043 Marburg Tel.:++49 (0) 6421-28 65000 Director: Professor Dr. Robert Grosse
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Clinical-theoretical Institutions
Emil von Behring-Library, Department of the History of Medicine
Research Group Professor Dr. Sahmland, background of the social, political, economical and Dr. K. Grundmann, Dr. U. Enke, N. Ulrich, M.A. scientific development in Germany‘s Imperial Era. The constitution of a pharmaceutical corporation by Main fields of research a scientist (Behringwerk, 1904) is a unique considerable feature. Due to the vast source Emil von Behring and his scientific work (Enke, materials Behring’s research can be newly evaluated Grundmann) in terms of science studies and become connected to History of Anatomy and the Anatomical a broadly based international scientist network. Collection in Marburg (Grundmann, Ulrich) Funded by DFG, EN 1068/2-1 – German Research History of the Hessian High Hospitals (Sahmland) Foundation Funding period 2014 – 2017 History of charitable and curing in-patient
Treatment in Hesse (Sahmland)
Research projects Title Provinience-research and digitalization of the General information about the institute objects of the Marburg Anatomical Collection Principal investigator(s) N. Ulrich Research funding 15.689,12 € Summary To this day, there has been no comprehensive digital collection catalogue of the Anatomical Collection at the University of Marburg. Most important publications The aims of the project are to profoundly file the Sahmland I (2013) Die Armenfürsorge in der entire collection and to gather information about at Elisabeth-Rezeption des 16. Jahrhunderts, in: Klaus least some prominent objects especially of the Bergdolt, Lothar Schmitt, Andreas Tönnesmann osteological collection. In cooperation with the (Hg.): Armut in der Renaissance (Wolfenbütteler Senckenberg-Museum in Frankfurt/M. these data Abhandlungen zur Renaissanceforschung, Bd. 30), are entered in the database Aquila. Wiesbaden, S. 159-185 Funded by FB 20, Philipps-University Marburg Funding period 2013 – 2016 Sahmland I (2013) Die Erfassung des Vorkommens des Cretinismus in Kurhessen 1856, in: Schriftenreihe Title Analysis, Digitalization and online-Presentation der Deutschen Gesellschaft für Geschichte der of the heritage of Emil von Behring Nervenheilkunde, Bd. 19, 2013, S. 263-286 Principal investigator(s) C. Friedrich, K. Grundmann, Konzeption und Ausführung einer neuen Behring- U. Enke & M. Kahler Ausstellung in der Bahnhofstraße 7 (Behring-Route): Summary In the project central sources of the Blut ist ein ganz besonderer Saft – Emil von Behring german history of medicine, pharmacy and science (1854 – 1917). Eröffnung Dezember 2013 were presented to the public and researchers as an (Grundmann) online-Database. Since May 2012, the digital copies of all hand-written manuscripts, pictures and Enke U (2014): Joseph Benedikt Kurigers embryo- historical business documents of the bacteriologist logische Wachstafel nach Soemmerring im Museum Emil von Behring (1854 – 1917) can be found on the Anatomicum Marburg, in: Tote Objekte – lebendige internet (www.uni-marburg.de/behring-digital). Geschichten. Exponate aus den Sammlungen der Funded by DFG, FR 887/4-1, 4-2, 4-3 – German Philipps-Universität Marbrug, Hrsg. I. Sahmland und Research Foundation K. Grundmann, Petersberg: 2014: S. 152-175 Funding period 2009 – 2013 Enke U (2014) Behrings Nachlässe – Behrings Title Biography of Emil von Behring (1854-1917) Biographien, in: Berichte zur Wissenschaftsge- Principal investigator(s) U. Enke schichte 37: S. 216-239 Summary Based on the digitalized heritage of Emil von Behring a biography of him as a person, a Grundmann K (2014) […] durch das Schwert vom scientist andan entrepreneur will be authored Leben zum Tode bringen […] – Schädel und according to present scientific standards. Main focus Totenmasken von hingerichteten Verbrechern in der will be laid on Behring’s personality, considering the Marburger Anatomischen Sammlung, in: Tote Objekte – lebendige Geschichten. Exponate aus den
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Sammlungen der Philipps-Universität Marburg, Hrsg. I. Sahmland und K. Grundmann, Petersberg: S. 55-77
Grundmann K (2014) Gesammeltes Wissen – Zur Geschichte des Sammelns, in: Schätze der Wissenschaft. Die Sammlungen, Museen und Archive der Philipps-Universität Marburg, Hrsg. Ch. Otterbeck, J. Schachtner, Marburg 2014, S. 17-24
Sahmland I (2014) Die stationäre karitative und medizinisch-kurative Versorgungslandschaft in Hessen vom Mittelalter bis ins 20. Jahrhundert. Vorstellung eines Forschungsvorhabens, in: Arno Görgen, Thorsten Halling (Hrsg.): Verortungen des Krankenhauses (Kultur Anamnesen. Schriften zur Geschichte und Philosophie der Medizin und der Naturwissenschaften, Bd. 6), Stuttgart: Steiner, S. 101-115
Sahmland I (2014) Das Elend der menschlichen Kreatur: das hockende Skelett in der Anatomischen Sammlung der Philipps-Universität Marburg, in: Tote Objekte – lebendige Geschichten. Exponate aus den Sammlungen der Philipps-Universität Marburg, Hrsg. I. Sahmland und K. Grundmann, Petersberg: 2014, S. 125-151
Contact Details: Bahnhofstr. 7, 35037 Marburg, Tel.:++49 (0) 6421-28 67088 Director: Professor Dr. Irmtraut Sahmland
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Institute of Clinical Cytobiology and Cytopathology
Research Groups Professor R. Lill Professor R. Jacob Title Role of iron-sulfur protein biogenesis in the regulation of cellular iron uptake and intracellular Main fields of research iron distribution Principal investigator(s) R. Lill Research in the institute aims to elucidate molecular Summary The link between mitochondrial Fe/S mechanisms of key cellular processes by using proteins biogenesis, cellular iron uptake and genetic, cell biological, biochemical and intracellular iron distribution is poorly understood to spectroscopic approaches. One focus of our work is date. In collaboration with TP A1 and A2 of SFB 593 on the biogenesis of iron-sulfur proteins in this project tries to elucidate these connections mitochondria, cytosol and nucleus and its links to using Saccharomyces cerevisiae and human cell cellular iron homeostasis and genome integrity. culture as model systems. Another topic analyzes protein sorting to the apical Funded by DFG, Research Training Group 1216, membrane of polarized cells. Biochemical and Intra- and intercellular transport and communication microscopic techniques are applied to unravel Funding period 2006 – 2015 cellular compartments, transport pathways and protein components involved in the trafficking of Title Iron-sulfur protein biogenesis in eukaryotes newly synthesized protein to the apical cell surface. Principal investigator(s) R. Lill Another focus is on the function of the transcription Summary We biochemically elucidate the function of factor Miz1. components involved in iron-sulfur cluster synthesis
and insertion into apoproteins in mitochondria, Research projects cytosol and nucleus of eukaryotic cells. We Title The role of mitochondria in the maturation of investigate the link of Fe/S protein biogenesis to cytosolic and nuclear iron-sulfur proteins DNA damage repair and genome maintenance Principal investigator(s) R. Lill mediated by the presence of Fe/S clusters in DNA Summary Mitochondria are essential cell organelles polymerases and helicases involved in the synthesis executing an indispensable function in the and repair of DNA. biogenesis of cytosolic and nuclear iron-sulfur (Fe/S) Funded by Max-Planck Society, Fellowship proteins. In this project we biochemically and Funding period 2009 – 2014 structurally characterize the components involved in the transport of a sulfur- and glutathione-containing Title Optimization of eukaryotic iron-sulfur protein compound to the cytosol to support cytosolic- biogenesis for biosynthetic purposes nuclear Fe/S protein maturation and other sulfur- Principal investigator(s) R. Lill requiring processes. Summary Iron-sulfur (Fe/S) proteins are functional Funded by DFG, SFB593 TP A1 – German Science as enzymes, electron carriers and sensors in a Foundation, Collaborative Research Centre 593 multitude of metabolic and regulatory reactions. We Funding period 2003 – 2014 try to better understand the function of the components involved in Fe/S protein biogenesis to Title Mechanism and Regulation of the Cellular use this knowledge for optimal maturation of Fe/S Compartmentalization of Iron between proteins that have been artificially introduced into Mitochondria and Cytosol cells as parts of newly constructed metabolic or Principal investigator(s) U. Mühlenhoff regulatory pathways. Summary The coordinated distribution of iron Funded by LOEWE Focus – Synthetische between intracellular compartments and the Mikrobiologie (SynMikro) adaptation of iron uptake to intracellular demands Funding period 2010 – 2015 are central for a balanced iron homeostasis. Mitochondria, the major iron-utilizing cell organelles, Title Sensing and intracellular delivery of iron in are critical regulators of cellular iron metabolism. fungi This project focuses on the role of mitochondria in Principal investigator(s) R. Lill & U. Mühlenhoff iron-responsive gene expression and the functional Summary The iron metabolism in fungi is regulated characterization of mitochondrial iron acquisition. on a transcriptional level and tightly linked to the Funded by DFG, SFB593 TP A2 – German Research biogenesis of iron-sulfur (Fe/S) proteins. We aim to Foundation, Collaborative Research Centre elucidate the molecular basis of this link by studying Funding period 2003 – 2014 how the iron-sensitive transcription factors respond
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Clinical-theoretical Institutions to changing iron concentrations. We have identified Summary Deletion of the Miz1 POZ domain in the cellular sensor for initiating the transcriptional Schwann cells induces a neuropathy in three month program for fungal high iron detoxification. old mice, with spontaneous partial remission after Funded by DFG, SFB 987 TP B2 – German Research one month. We have documented the pathology of Foundation, Collaborative Research Centre the nerve tissue. We unravel the molecular basis of Funding period 2012 – 2016 this neuropathy to find target proteins for therapeutic approaches. We are interested in the Title Role of redox-active thiols in the biogenesis of regeneration of nerve tissue which accompanies cytosolic and nuclear iron-sulfur proteins dysmyelination. Principal investigator(s) R. Lill Funded by DFG, EL 125/6-1 – German Research Summary Fe/S protein biogenesis is a complex Foundation process requiring numerous components in Funding period 2013 – 2016 mitochondria and cytosol. This proposal is centered on the thiol – metal-thiolate switch occurring during Fe/S protein assembly in the cytosol-nucleus of eukaryotes. In particular, the proposal addresses the General information about the institute role of a hyper-reactive Cys residue of the CIA protein Cia2 which is essential for cell viability. Research funding 3.055.769,08 € Funded by DFG, SPP 1710 – German Research Foundation Funding period 2012 – 2016 Most important publications Title Identification of vesicle components involved in Stehling O, Mascarenhas J, Vashisht AA, Sheftel AD, apical protein transport Niggemeyer B, Rösser R, Pierik AJ, Wohlschlegel JA, Principal investigator(s) R. Jacob Lill R (2013). Human CIA2A-FAM96A and CIA2B- Summary Polarized epithelial cells contain a plasma FAM96B integrate iron homeostasis and maturation membrane that is divided into two separate of different subsets of cytosolic-nuclear iron-sulfur compartments. Each membrane compartment is proteins. Cell Metab 18: 187-198 composed of distinct proteins and lipids, which are sorted by specific mechanisms into the correct Straube T, von Mach T, Hönig E, Greb C, Schneider D, membrane domain. Compartments that are Jacob R (2013) pH-dependent recycling of galectin-3 traversed by these pathways as well as the at the apical membrane of epithelial cells. Traffic implicated protein- and lipid-components will be 14:1014-1027 analyzed in this project. Funded by DFG, SFB593 TP A9 – German Research Weber M, Gawanbacht A, Habjan M, Rang A, Borner Foundation, Collaborative Research Centre C, Schmidt AM, Veitinger S, Jacob R, Devignot S, Funding period 2005 – 2014 Kochs G, García-Sastre A, Weber F (2013) Activation of RIG-I by incoming RNA virus nucleocapsids Title Characterisation of motor proteins involved in containing a 5’-triphosphorylated genome. Cell Host apical targeting & Microbe 13: 336-346 Principal investigator(s) R. Jacob Summary For apical protein trafficking lipid raft- Srinivasan V, Pierik AJ, Lill R (2014) Crystal structures dependent and -independent sorting has been of nucleotide-free and glutathione-bound described. The sorting mechanism itself, interactions mitochondrial ABC transporter Atm1. Science between clusters within vesicular lumina and 343:1137-1140 components on the cytosolic surface of newly formed vesicles are completely unknown. Especially Webert H, Freibert SA, Gallo A, Heidenreich T, Linne motor proteins that are required for apical vesicle U, Amlacher S, Hurt E, Mühlenhoff U, Banci L, Lill R transport remain to be identified. Their (2014) Functional reconstitution of mitochondrial characterization is the main focus of this research Fe/S cluster synthesis on Isu1 reveals the project. involvement of ferredoxin. Nat Commun 5:5013 Funded by DFG, Research Training Group 1216, Intra- and intercellular transport and communication Paul V, Lill R (2014) Snapshot: Eukaryotic Fe-S Funding period 2006 – 2015 Protein Biogenesis. Cell Metab 20:384
Title Late onset neuropathy in mice lacking Hoff F, Greb C, Hollmann C, Hönig E, Jacob R (2014): functional Miz1 in Schwann cells The large GTPase Mx1 is involved in apical transport Principal investigator(s) H.P. Elsässer of MDCK cells. Traffic 15:983-996
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Clinical-theoretical Institutions
Sanz-Moreno A, Fuhrman D, Zankel A, Reingruber H, Kern L, Meijer D, Niemann A, Elsässer H-P (2014) Late onset neuropathy with spontaneous clinical remission in mice lacking the POZ domain of the transcription factor Myc-interacting-zinc-finger- protein 1 (Miz1) in Schwann cells. J Biol Chem 10.1074/jbc.M114.605931
Contact Details: Robert-Koch-Str. 6, 35039 Marburg, Tel.:++49 (0) 6421-28 66483 Director: Professor Dr. Roland Lill
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Clinical-theoretical Institutions
Institute of Immunology
Research Groups Professor S. Bauer Summary This project focuses on the function of the Professor M. Schnare, Professor M. Bacher, Dr. TLR/interleukin-1 receptor / (TIR) family during P. Yu, Dr. A. Kaufmann pneumonia. ST2 and TIR8 (SIGIRR) have been implicated in the negative control of PRR-mediated
inflammatory responses and/or promotion of repair Main fields of research processes. ST2 serves as a receptor for the DAMP IL- Research activities of the Institute for Immunology 33 and is involved in recruiting type 2 innate encompass innate immune recognition of lymphoid cells (ILC2) that in turn might regulate endogenous retroviruses and nucleic acids derived healing processes in the lung. We will investigate the from pathogens, the function of antimicrobial role of ST2 in regulation the sub-acute phase of proteins during inflammation, IgE regulation and bacterial pneumonia after detection of the DAMP IL- immunological aspects of neuroinflammation in 33. Furthermore, the requirements and ligands for early Alzheimers disease. the immune-regulatory function of TIR8 during pneumonia will be analyzed. Research projects Funded by DFG, SFB/TR84 – German Research Title Generation and characterization of a RIG-I Foundation, Transregional Collaborative Research ligand derived from endogenous RNA by RNase Centre 84 digestion Funding period 2014 – 2018 Principal investigator(s) A. Kaufmann & S. Bauer Summary RNase-digested self-RNA acts in addition Title Development and function of respiratory to exogenous viral RNA as ligand for the cytoplasmic macrophages and dendritic cell subsets during RNA sensor RIG-I. This immunostimulatory potential bacterial pneumonia is triggered by a distinct structure generated by Principal investigator(s) S. Bauer, H. Hackstein digestion with single-strand specific RNases (e.g. (UKGM, Giessen) & J. Lohmeyer (UKGM, Giessen) RNase L, RNase I). In this study we have started to Summary Bacterial pneumonia is a leading cause of identify the RIG-I-activating structure and sequence community acquired as well as nosocomial infections of self-RNA by next generation sequencing. and death. Lung resident dendritic cells (DC) and Funded by DZIF – German Centre for Infection macrophages (MP) recognize bacterial pathogens, Diseases initiate immune responses and regulate Funding period until 2015 inflammation. Several DC subsets, such as CD103+ and CD103- conventional migratory DCs (cDCs), Title Role of the RNA modifications 2’-O-methylation monocyte-derived DCs (moDCs) and plasmacytoid and N6-methyladenosine in viral pathogenicity DCs as well as functionally distinct lung MP Principal investigator(s) S. Bauer populations have been described but their precise Summary Since RNA modifications such as 2’-O- contribution to the respiratory immune response methylation and N6-methyladenosine negatively during bacterial infections remains unresolved. We modulate Toll-like receptor 7-mediated immune will address the role of DC and MP subsets and the recognition of RNA, we will investigate if influenza mechanism of ADAR1-dependent DC and MP virus genomic RNA is 2’-O-methylated and what role development in immune responses in the lung. N6-methyladenosine in influenza mRNA may play for Funded by DFG, SFB/TR84 – German Research viral pathogenicity, infectivity and immune Foundation, Transregional Collaborative Research recognition. In addition, we will analyze a possible Centre 84 antagonistic function of 2’-O-methylated host cell Funding period 2014 – 2018 tRNA associated with VSV or SeV in early immune escape from TLR7 recognition in plasmacytoid Title Macrophage migration inhibitory factor and dendritic cells. neuroinflammation in early Alzheimers disease Funded by DFG, SFB 1021 – German Research Principal investigator(s) M. Bacher Foundation, Collaborative Research Centre 1021 Summary One major aim of this proposal is to Funding period until 2016 evaluate whether the early and sustained increase of MIF might be an important trigger for Title Role of innate immune receptors in preventing neuroinflammatory processes during the progress of hyper-inflammation and promoting repair during the neurodegeneration in Alzheimer’s dementia. To bacterial pneumonia achieve this goal, we plan to use in vitro experiments Principal investigator(s) S. Bauer & B. Opitz (Charité with primary neuronal and microglia cell cultures, Berlin) and we would like to substantiate our findings by
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Clinical-theoretical Institutions experiments using transgenic APP mouse models. General information about the institute Funded by DFG – German Research Foundation Funding period until 2015 Research funding 1.386.470,14 €
Title The B cell response against Endogenous Retrovirus Most important publications Principal investigator(s) P. Yu Lübben W, Turqueti-Neves A, Okhrimenko A, Stöberl Summary We have demonstrated that nucleic acid C, Schmidt V, Pfeffer K, Dehnert S, Wünsche S, recognizing Toll-like receptors (TLR) 3, -7 and -9 are Storsberg S, Paul S, Bauer S, Riethmüller G, an essential component of the defense against Voehringer D, Yu P (2013) IgE knock-in mice suggest endogenous retroviruses. Surprisingly it seems that a role for high levels of IgE in basophil-mediated the TLR7 mediated activation of the endogenous active systemic anaphylaxis. Eur J Immunol 43 retrovirus specific immune response is most (5):1231-42 essential for protection. We are currently establishing a in vitro B cell model to dissect the B Noelker C, Stuckenholz V, Reese JP, Alvarez-Fischer cell receptor-TLR interactions, in order to D, Sankowski R, Rausch T, Oertel WH, Hartmann A, understand the role of B cells in protection against van Patten S, Al-Abed-Y, Bacher M (2013) CNI-1493 endogenous and exogenous retroviruses. attenuates neuroinflammation and dopaminergic Funded by DFG – German Research Foundation neurodegeneration in the acute MPTP mouse model Funding period 2014 – 2016 of Parkinson's disease. Neurodeg Dis 12:103-10
Czudai-Matwich V, Schnare M, Pinkenburg O (2013) Title Analysis of the role of IgE in an in vivo model of A simple and fast system for cloning influenza A virus systemic lupus erythematosous gene segments into pHW2000- and pCAGGS-based Principal investigator(s) P. Yu vectors. Arch Virol 58(10):2049-58 Summary IgE production is tightly regulated and normally associated with allergic diseases. However Atanasova S, Hirschburger M, Jonigk D, Obert M, recently evidence in humans and mouse models Petri K, Evers A, Hecker A, Schmitz J, Kaufmann A, arose, which suggests that IgE could play an effector Wilhelm J, Chakraborty T, Warnecke G, Gottlieb J, or modulator role in autoimmunity. To study this Padberg W, Grau V (2013) A relevant experimental hypothesis, we have generated double mutant mice, model for human bronchiolitis obliterans syndrome. which display a genetically enhanced IgE immune J Heart Lung Transplant 32(11):1131-9 response and are prone to develop lupus-like Roettger Y, Du Y, Bacher M, Zerr I, Dodel R, Bach JP autoimmunity. We are currently studying the (2013) Immunotherapy in Prion Diseases. Nat Rev histochemical and immunological changes in the Neurol 9:98-105 target organ kidney and secondary lymphatic organs. These studies have the potential to further our Reimer E, Somplatzki S, Zegenhagen D, Hänel S, Fels understanding of B cell mediated autoimmunity by A, Bollhorst T, Hovest LG, Bauer S, Kirschning CJ, establishing a pathogenic link between IgE and lupus Böldicke T (2013) Molecular cloning and inflammation. characterization of a novel anti-TLR9 intrabody. Cell Funded by Philipps University Marburg & Thyssen Mol Biol Lett 18(3):433-46 Foundation Schwartz C, Turqueti-Neves A, Hartmann S, Yu P, Funding period 2013 – 2015 Nimmerjahn F, Voehringer D (2014) Basophil-
mediated protection against gastrointestinal Title The influence of bactericidal/permeability- helminths requires IgE-induced cytokine secretion. increasing protein (BPI) and BPI-related proteins on PNAS 111 (48):E5169-77 the infectivity on human pathogenic viruses Principal investigator(s) M. Schnare Martins M, McCarthy A, Baxendale R, Guichard S, Summary The release of antimicrobial products Magno L, Kessaris N, El-Bahrawy M, Yu P, Katan M prevents the uncontrolled growth and spread of (2014) Tumor suppressor role of phospholipase C pathogens within the host. Besides their well epsilon in Ras-triggered cancers. PNAS 111 (11): characterized function in controlling bacterial 4239-44 infections different antimicrobial proteins and peptides display antivirus activity as well. We investigate the role of the antimicrobial protein Contact Details: BPI and BPI-related proteins in the control of virus Biomedical Research Centre (BMFZ) replication and the underlying molecular Hans-Meerwein-Str. 2, 35032 Marburg, mechanisms. Tel.:++49 (0) 6421-28 66493 Funded by von Behring –Röntgen Foundation Director: Professor Dr. Stefan Bauer Funding period until 2016
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Clinical-theoretical Institutions
Institute of Medical Microbiology and Hospital Hygiene
Research Group Professor M. Lohoff Tackenberg B, Kamradt T, Lohoff, M (2013) Pathogenic IL-17A-dependent help of Tc17 cells for Main fields of research Th17 cells to initiate autoimmune encephalomyelitis. We are focused on the regulation CD4+ T-cell subset J Clin Invest 123:247-260 differentiation, particularly on the role of IRF transcription factors. We have previously shown that Abass E, Bollig N, Reinhard K, Camara B, Mansour D, IRF4 is mandatory for generating the subsets Th2, Visekruna A, Lohoff M, Steinhoff U (2013)rKLO8, a Th9, Th17 and Tfh cells. During this research period, Novel Leishmania donovani–Derived Recombinant we have demonstrated a novel crucial role of IRF4 Immunodominant Protein for Sensitive Detection of for developing the low cytotoxic CD8+ T cell Visceral Leishmaniasis in Sudan. PLOS Neglected subpopulation Tc17. Furthermore, we have Tropical Diseases 7:1-10 delineated a reversed helper function of Tc17 cells for CD4+ T cells during autoimmunity of the central Huber M, Lohoff M (2013) IRF4 Provides Rations for nervous system. Currently, we mutagenize IRF4 to Cytotoxic CD8(+) T Cell Soldiers. Immunity 39(5):797- test, if particular parts of IRF4 are responsible for 9 selective functions among those mentioned. Grusdat M, McIlwain DR, Xu HC, Pozdeev VI,Knievel Research projects J, Crome SQ, Robert-Tissot C, Dress RJ, Pandyra AA, Title Analysis of the role of the transcription factor Speiser DE, Lang E, Maney SK, Elford AR, Hamilton IRF4 for T lymphocyte subset differentiation SR, Scheu S, Pfeffer K, Bode J, Mittrucker H.-W., Principal investigator(s) M. Lohoff Lohoff M, Huber M, Haeussinger D, Ohashi PS, Mak Summary We have shown that IRF4 is crucial for TW, Lang KS, Lang PA (2014) IRF4 and BATF are developing the Tc17 subset among CD8+ cells, which critical for CD8T-cell functionfollowing infection with lacks cytotoxicity but, as we showed, has an LCMV. Cell Death and Differentiation 21:1050-1060 unexpected helper function for CD4+ T cells. These data revers the common dogma of CD4+ helper Huber M, Lohoff M (2014) IRF4 at the crossroads of function for development of CD8+ T cell functions. effector T-cell fate decision. Eur J Immunol Funded by DFG – German Research Foundation, von 44(7):1886-95 Behring-Röntgen Foundation Funding period DFG unitl 2014 von Behring-Röntgen Foundation until 2016 Research Goup PD M. Huber
Title Analysis of functional modules of IRF4 with Main fields of research mutually exclusive sub-functions in CD4+ T cells Our group is focused on the molecular regulation Principal investigator(s) M. Lohoff CD4+ and CD8+ T-cell differentiation and function in Summary We have shown that retroviral protective and pathologic immune responses. During overexpression of IRF4 rescues the IRF4- dependent the research period (2013/2014), our group has functions in T cells from IRF4 – deficient mice. demonstrated a crucial role of the transcription Currently, we attempt to insert mutations into the factor interferon regulatory factor (IRF)4 for the IRF4 gene and overexpress these altered IRF4 development of the cytotoxic T lymphocytes (CTL)s molecules in comparison to normal IRF4. The aim of and for “low” cytotoxic CD8+ T cell subpopulations the study is to identify critical functional modules of including Tc9 and Tc17 cells. Furthermore, we have IRF4 which, if destroyed, create an IRF4 molecule delineated the supportive function of low cytotoxic with more specific sub-functions such as the capacity Tc9 and Tc17 cells for CD4+ T cell activity in allergic to support differentiation of only one T cell subset, airway disease and autoimmunity of the central but not others. nervous system, respectively. Funded by CholHo Funding period 2014 – 2016 Research projects
Title Analysis of the role of the transcription factor
IRF4 for cytotoxic T lymphocyte effector function Most important publications and memory development Huber M, Heink S, Pagenstecher A, Reinhard K, Ritter Principal investigator(s) M. Huber J, Visekruna A, Guralnik A, Bollig N, Jeltsch K, Summary We have shown that IRF4 is crucial for the Heinemann C, Wittmann E, Buch T, Prazeres da Costa protective CD8+ T-cell response to the bacterium O, Brüstle A, Mak TW, Brenner D, Mittrücker HW,
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Listeria monocytogenes (Lm). Although dispensable (2013) Tc9 cells, a new subset of CD8+ T cells, for early activation, IRF4 was essential for support Th2-mediated airway inflammation. Eur J establishment of fully functional effector and Immunol 43:606-618 Article selected for “In this memory pool. IRF4 regulated these functions, acting issue” section of EJI. as both transcriptional repressor and activator. The direct positive regulation of Prdm1 gene expression Huber M, Heink S, Pagenstecher A, Reinhard K, Ritter contributed to the IRF4 effects. J, Visekruna A, Guralnik A, Bollig N, Jeltsch K, Funded by DFG – German Research Foundation Heinemann Ch, Wittmann E, Buch T, Prazeres da Funding period 2010 – 2015 Costa O, Brüstle A, Brenner D, Mak TW, Mittrücker H- W, Tackenberg B, Kamradt T, Lohoff M (2013) Title Analysis of the role of the transcription factor Pathogenic IL-17A-dependent help of Tc17 cells for IRF4 for Tc17 effector function in autoimmune Th17-mediated autoimmune encephalomyelitis. J encephalomyelitis Clin Invest 123:247-260 Article recommended by Principal investigator(s) M. Huber Faculty of 1000, ranking: exceptional. Summary We have shown that IRF4 is required for the development of IL-17-producing CD8+ T (Tc17) Huber M; Lohoff M (2014) IRF4 at the crossroad of cells. IRF4 regulated Tc17 differentiation by effector T-cell fate decision. Eur J Immunol 44:1886- balancing the levels of TFs crucial for type 17, Treg 95 and CTL- differentiation. A novel function of CD8+ T cells became obvious, because IRF4-sufficient Tc17 Mittrücker H-W, Visekruna A, Huber M (2014) cells provided “reverse help” via cell-associated IL- Heterogeneity in the differentiation and function of 17A to CD4+ T cells for Th17-mediated CD8+ T cells. Arch. Immunol Ther Exp 62:449-58 encephalomyelitis. Funded by DFG – German Research Foundation and Pick J, Arra A, Lingel H, Hegel JK, Huber M, Nishanth BiogenIdec G, Jorch G, Fischer K-D, Schlüter D, Tedford K, Funding period 2010-2015, 2014-2016 Brunner-Weinzierl MC (2014) CTLA-4 (CD152) enhances the Tc17 differentiation program. Eur J Title Analysis of the role of the transcription factor Immunol 44:2139-52 IRF4 for Tc9 effector function in allergic airway disease Grusdat M, McIlwain DR, Xu HC, Pozdeev VI, Knievel Principal investigator(s) M. Huber J, Crome SQ, Robert-Tissot C, Dress RJ, Pandyra AA, Summary We have demonstrated that murine CD8+ Speiser DE, Lang E, Maney SK, Elford AR, Hamilton T cells activated in the presence of IL-4 plus TGF- SR, Scheu S, Pfeffer K, Bode J, Mittrücker HW, Lohoff develop into transient IL-9 producers (Tc9 cells) M, Huber M, Häussinger D, Ohashi PS, Mak TW, Lang characterized by low cytotoxic function. These cells KS, Lang PA (2014) IRF4 and BATF are critical for required STAT6 and IRF4 for the differentiation and CD8+ T-cell function following infection with LCMV. displayed a supportive function in Th2-dependent Cell Death Differ 21:1050-60 airway inflammation. This suggests that Tc9 cells might be a therapeutic target in allergic disorders. Funded by DFG – German Research Foundation Research Group Professor Steinhoff Funding period 2010 – 2015 Main fields of research Investigation of anti-inflammatory control Most important publications mechanisms in the intestine. Our research focuses Huber M, Lohoff M (2013) IRF4 provides rations for mainly on three main topics, i.e. a) the impact of cytotoxic CD8+ T cell soldiers. Immunity 39:797-59 normal dietary proteins on maintenance of intestinal homeostasis and regulation of inflammatory Raczkowski F, Ritter J, Heesch K, Schumacher V, responses b) the effects of short chain fatty acids Höcker L, Raifer H, Klein M, Bopp T, Harb H, Kesper produced by intestinal bacteria on regulatory T cells DA, Pfefferle PI, Grusdat M, Lang PA, Mittrücker H-W and c) the importance of the intestinal microflora on and Huber M (2013) The transcription factor intraluminal anti-bacterial defense against interferon regulatory factor 4 controls peripheral enteropathogenic E. coli. + CD8 T cell differentiation. Proc Natl Acad Sci USA 110:15019-24 Research projects Title Control of intestinal inflammation by food and Visekruna A, Ritter J, Scholz T, Campos L, Guralnik A, intestinal microflora Poncette L, Raifer H, Hagner-Benes S, Garn H, Staudt Principal investigator(s) A. Visekruna, Anton Volkov V, Bopp T, Reuther S, Taube Ch, Loser K, Huber M & U. Steinhoff
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Summary Normal dietary proteins activate T cells predominantly in Peyer´s patches of the gut. These Contact Details: cells remain innocuous because they will die after Biomedical Research Centre (BMFZ) activation and removal of such dead T cells is crucial Hans-Meerwein-Str. 2, 35043 Marburg, for the production of anti-inflammatory substances. Tel.:++49 (0) 6421-28 66455 Accordingly, animals fed with a protein-free diet Director: Professor Dr. Michael Lohoff proteins by amino acids are highly susceptible to inflammation. Funded by von Behring-Röntgen Foundation –and LOEWE Centre – UGMLC; German Science Foundation – Collaborative Research Centre SFB 650 Funding period 2012 – 2015
Most important publications Volkov A, Hagner S, Löser S , Raifer H, Hellhund A, Garn H, Steinhoff U 5i Subunit Deficiency of the Immunoproteasome Leads to Reduced Th2 Response in OVA Induced Acute Asthma. PLoS One 4, 8(4):e60565
Abass E, Bollig N, Reinhard K, Camara B, Mansour D, Visekruna A, Lohoff M, Steinhoff U (2013) rKLO8, a novel Leishmania donovani - derived recombinant immunodominant protein for sensitive detection of visceral leishmaniasis in Sudan. PloS Negl Trop Dis 18;7:e2322
Mittrücker H-W, Seidel D, Bland PW, Zarzycka A, Kaufmann SHE, Visekruna A, Steinhoff U (2014) Reduced innate and enhanced adaptive immunity against Listeria monocytogenes infection in germfree mice. Eur J Immunol 44:1710-5
Visekruna A, Linnerz T, Martinic V, Vachharajani N, Hartmann S, Harb H, Joeris T, Pfefferle P, Hofer J, Steinhoff U (2014) Transcription factor c-Rel plays a crucial role in driving anti-CD40-mediated innate colitis. Mucosal Immunology 8(2):307-15
Yun Y, Srinivas G, Kuenzel S, Linnenbrink M , Bruce K, Steinhoff U, Baines JF, Schaible U (2014) Environmentally determined differences in the murine lung microbiota and their relation to alveolar architecture. PLoS One 9 (12):e113466
Abass E, Martinkovic F, Semiao-Santos SJ, Sundar S, Walden P, Piarroux R, el Harith A, Lohoff M, Steinhoff, U (2014) Heterogeneity of Leishmania Donovani parasites complicates diagnosis of visceral Leishmaniasis: Comparison of different serological tests in three endemic regions. Plos One Accepted
General information about the institute
Research funding 496.707,62 €
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Institute of Virology
Research group Professor Becker
Main fields of research Research performed at the Institut für Virologie mainly focuses on highly pathogenic viruses that can be transmitted from animal to man. Examples are viruses causing fulminant hemorrhagic fevers, (Marburg virus, Lassa virus, Rift Valley Fever virus), highly pathogenic influenza virus (bird flu), Nipah virus, SARS and others. Work with those viruses is performed under highest safety conditions in a modern BSL-4 laboratory. With this laboratory, Marburg University represents a unique academic competence center for diagnostics and research on highly O-glycosylated which is a rare feature. We highly pathogenic viruses. Researchers at the Institut produced a mutant surface protein missing the O- für Virologie are interested in interactions between glycan attachment sites and test its function in cell viruses and the host that determine pathogenicity of culture. Surprisingly, the missing O-linked sugars the pathogen. The work group Parasitology within which represent approximately 50% of the molecular the Institut für Virologie carries out studies to mass did neither impair intracellular transport nor characterize biosynthetic pathways in plasmodia, receptor recognition. Further on, recombinant trypanosomes and toxoplasma. Marburg virus missing the O-glycosylation was constructed and rescued. Characterization of the Research projects virus is ongoing. Funded by Leibniz Graduate School for Emerging Title Deutsches Zentrum für Infektionsforschung Infections (EIDIS) (DZIF) – TTU Emerging Infections Funding period 2012 – 2015 Principal investigator(s) S. Becker
Summary The German Centre for Infectious research Title Morphogenesis and transport of filovirus (DZIF) is one of the health centers for translational nucleocapsids research funded by the federal ministry of research. Principal investigator(s) S. Becker & O. Dolnik The section Emerging Infections, coordinated by the Summary Marburg virus replication in cells results in Institute of Virology, focuses on the development of formation of inclusions in the cytoplasm. Inclusions diagnostics, emergency vaccines and antivirals represent sites of nucleocapsid morphogenesis, viral against novel viruses. In Marburg we develop and replication and transcription. We investigate the test two platforms for rapid vaccine development structure and formation of inclusions and and establish animal models to be used in cases of nucleocapsids and how mature nucleocapsids are emergencies under highest safety precautions (BSL.- transported to the sites of budding. Live cell imaging 4). In the funding period 2013 - 2015 one vaccine was established for fluorescent viruses under BSL-4 platform (recombinant influenza virus) was conditions. Thereby identified interfaces between established and emergency vaccines against MERS cellular and viral proteins may represent targets for coronavirus were tested for immunogenicity and antiviral intervention. efficacy. Funded by DFG, SFB 593, TPB12 – German Research Funded by BMBF – Federal Ministry of Education Foundation, Collaborative Research Centre 593 and Research Funding period 2011 – 2014 Funding period 2013 – 2015
Title Quality Assurance Exercises and Networking on Title The role of O-glycosylation of the Marburg virus the Detection of Highly Infectious Pathogens surface glycoprotein GP (Quandhip) Principal investigator(s) S. Becker Principal investigator(s) S. Becker & M. Eickmann Summary Viral surface glycoproteins represent the Summary The Joint Action (JA) aims to link and communication interface between the virus and the consolidate the objectives of two existing networks host. These molecules mediate receptor recognition (EQADeBa and ENP4-Lab). The primary objective of and fusion with the host cell membranes. The the current application is to stabilise both network surface glycoproteins of Marburg and Ebola virus are activities that link 33 partners from 21 European
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Clinical-theoretical Institutions countries highly specialised and advanced Funding period: 2012 – 2015 laboratories. This will ensure the universal exchange of best diagnostic strategies able to support a Title Regulation der filoviralen RNA-Synthese European response strategy to outbreaks of highly Principal investigator(s) S. Becker, R. Hartmann pathogenic infectious agents plus generating a (Pharm. Chemie) biodiverse repository of reference materials. The JA Summary: Filovirus transcription is dependent on a will provide a supportive European infrastructure filoviral-specific transcription factor VP30. The and strategy for bacterial antibiotic susceptibility mechanism of how VP30 regulates viral transcription testing, training, and external quality assurance and replication is unknown. This project aims at exercises (EQAE) according to biosafety and elucidating the composition and function of the viral biosecurity review of current practices. transcriptase in complex with the viral genome. The Funded by EU focus of the current funding period is the interaction Funding period 2011 – 2014 between VP30 and the viral RNA. Title European Infrastructure on highly pathogenic Funded by DFG, SFB 1021, TP A02 – German agents (ERINHA) Research Foundation, Collaborative Research Centre Principal investigator(s) S. Becker & M. Eickmann 1021 Summary ERINHA aims to build a pan-European Funding period 2013 – 2016 research infrastructure aiming to reinforce the European coordination and capacities for the study Title Die Adaption von Marburg Virus und Nagetiere and the surveillance of highly pathogenic micro- als Modell für virale Pathogenese organisms. The ERINHA infrastructure will provide Principal investigator(s) S. Becker access to state-of-the-art BSL4 facilities for the Summary: While Marburg virus is lethal for humans European scientific community to enhance basic and and non-human primates, infection of rodents finalised research activities and diagnostic activities results in no disease. Only after adaptation, Marburg Funded by EU virus becomes pathogenic for rodents. Using the Funding period 2010 – 2013 guinea pig model, pathogenicity factors of Marburg virus are investigated comparing guinea pig adapted Title Comparative analyses of nucleoproteins of and non-adapted viruses. Arenaviruses Funded by DFG, SFB 1021, TP B03 – German Principal investigator(s) S. Becker & S. Wolff Research Foundation, Collaborative Research Centre Summary Characterisation of the nucleoprotein NP 1021 derived from Junin (JUNV) and Tacaribe (TCRV), Funding period 2013 – 2016 which are closely related and prototypes for HF- causing and non-pathogenic New world Title Investigations of filovirus propagation and arenaviruses. Main focus is the identification and cellular defense mechanisms… analysis of motifs within NP for their effect on viral Principal investigator(s) S. Becker transcription/replication and budding, in particular Summary: Bats are considered to represent the with respect to the involvement of putative late natural reservoir of filoviruses. After infection, bats domains and caspase cleavage sites. replicate and shed the filoviruses without developing Funded by Manchot-Foundation disease. Humans, however, succumb to the disease. Funding period 2010 – 2013 It is therefore of interest to compare the cellular response of bats and humans to filovirus infection in Title Analysis of host cell proteins for the order to understand pathogenicity mechanisms that intracellular transport of Marburg virus lead to the severe course of disease in humans. nucleocapsids Funded by DFG, Be 1325/6-1 – German Research Principal investigator(s): S. Becker & M. Klüver Foundation Summary The surface of Marburg virus Funding period 2013 – 2015 nucleocapsids is covered with the proteins VP30, VP35, VP24 and L and it cannot ruled out that one or more of these proteins is involved in transport Research group Dr. Friebertshäuser processes and interactions with the cytoskeleton. Professor Garten Therefore this project focuses on identification of cellular interaction partners of the Marburg virus Research projects proteins VP30, VP35, VP24 and L by using yeast two- Title Proteases of the respiratory tract activating hybrid screenings. Special attention is paid on motor human influenza viruses: identification, proteins and proteins involved in intracellular characterization and cellular compartmentation transport processes. Afterwards found interactions Principal investigator(s) E. Friebertshäuser & W. will be characterised more into detail. Garten Funded by: Manchot Foundation
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Clinical-theoretical Institutions
Summary The trypsin-like proteases HAT and Research group Professor Klenk TMPRSS2 activate human influenza viruses in the respiratory tract. TMPRSS2 cleaves the viral surface Research projects glycoprotein hemagglutinin (HA) intracellular before Title New drugs targeting influenza virus polymerase the virus is assembled, whereas HAT cleaves HA0 of Principal investigator(s) H. D. Klenk virions upon entry into target cells and during HA is Summary Adaptation of avian influenza viruses to a synthesized within the host cell. Moreover, TMPRSS2 mammalian host is mediated by mutations in the and HAT differ in their distribution in the upper and viral polymerase. Recombinant viruses have been lower respiratory tract with TMPRSS2 being present generated to analyze the role of these mutations in along the respiratory tract, whereas HAT is the interaction with host proteins as well as their expressed in the upper airways, trachea and bronchi, effects on polymerase activity, virus replication and but not in the lung. Using TMPRSS2-knockout mice pathogenicity. we were able to demonstrate that TMPRSS2 is a host Funded by EU (FLUPharm) cell factor that is essential for pneumotropism and Funding period 2011 – 2014 pathogenicity of human H1N1 and H7N9 influenza viruses in mice. Development of specific TMPRSS2 Title Interaction of the influenza virus polymerase inhibitors is ongoing in our lab. with host factors and its role in pathogenesis and Funded by SFB 593 TP B2 – German Research host adaptation Foundation, Collaborative Research Centre 593 Principal investigator(s) H. D. Klenk Funding period 2011 – 2014 Summary Host range and pathogenicity of influenza viruses depend on interactions of viral proteins with Title Proteolytic activation of influenza viruses by host factors preferentially at borders between matriptase different cell compartments. The project is focused Principal investigator(s) E. Friebertshäuser & A. on the interaction of the viral polymerase with the Arendt nuclear import machinery of the host cell and of the Summary Cleavage of the influenza virus surface viral hemagglutinin with host proteases. glycoprotein hemagglutinin (HA) by host cell Funded by DFG, SFB 593, TP B1 – German Research proteases is essential for virus infectivity. H9N2 Foundation, Collaborative Research Centre 593 viruses vary remarkably in the amino acid sequence Funding period 2011 – 2014 at the HA cleavage site, and many isolates from Asia and the Middle East possess unusual multibasic motifs. The protease matriptase can activate H9N2 Research group Professor Maisner viruses at such motifs and thereby supports proteolytic activation in a wide range of tissues what Research projects may affect virus spread, tissue tropism and pathogenicity. Title Role of the matrix protein in Nipah virus Funded by von Behring-Röntgen-Stiftung infection of polarized epithelial cells Funding period 2012 – 2014 Principal investigator(s) A. Maisner & Erik Dietzel Summary Entry and exit from polarized epithelia in Title Activation of influenza viruses by proteases lungs and kidneys crucially influence spread of highly from host cells and bacteria in the human airway pathogenic Nipah viruses within the host, and epithelium determine host-to-host transmission. Aim of this Principal investigator(s) E. Friebertshäuser project is to elucidate the molecular basis of the Summary Bacterial co-infections by S. aureus or S. apical transport of the viral matrix protein leading to pneumoniae contribute significantly to morbidity targeted apical virus release from polarized and mortality of influenza infections. Interestingly, epithelia. certain bacteria have been demonstrated to support Funded by DFG, MA-1886/6-1 – German Research activation of the influenza virus hemagglutinin (HA) Foundation either by secreting proteases that cleave HA or due Funding period 2010 – 2013 to activation of cellular HA-cleaving proteases, and thereby may support virus spread and enhanced Title Role of the matrix protein in Nipah virus pathogenicity. We aim to identify bacterial proteases infection of polarized epithelial cells that support HA activation upon co-infection in the Principal investigator(s) A. Maisner & Boris Lamp airway epithelium. Development of specific protease Summary Entry and exit from polarized epithelia in inhibitors may lead to novel drugs for the treatment lungs and kidneys crucially influence spread of highly of viral-bacterial co-infections. pathogenic Nipah viruses within the host, and Funded by Universities Giessen and Marburg Lung determine host-to-host transmission. Aim of this Center (UGMLC) project is to elucidate the molecular basis of the Funding period 2013 – 015 apical transport of the viral matrix protein leading to
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Clinical-theoretical Institutions targeted apical virus release from polarized Funded by DFG, SFB 593 (Project B11) – German epithelia. Research Foundation, Collaborative Research Centre Funded by DFG, MA-1886/6-2 593 Funding period 2014 – 2016 Funding period 2011 – 2014
Title Nipah virus infection of polarized epithelial cells Title Proteolytic activation and endosomal trafficking Principal investigator(s) A. Maisner & Laura Behner of the Nipah virus fusion protein Summary Nipah virus spread in polarized epithelial Principal investigator(s) A. Maisner & T. Freitag cell monolayers is always characterized by rapid Summary To elucidate the molecular basis of the virus-mediated cell-to-cell fusion. To elucidate the high pathogenicity of Nipah viruses, the project molecular mechanisms induced by the fusion- focus on the endosomal trafficking of the F protein mediated cytopathic effect, the influence of NiV and subsequent cathepsin cleavage in the absence glycoproteins F and G on the actin cytoskeleton and or presence of other viral envelope proteins (G and the epithelial barrier function is analyzed. M). Inhibitors either blocking F trafficking or the Funded by DFG, GK 1216/2 (Project B.8) – German proteolytic activity of endosomal cathepsin L and B Research Foundation, Research Training Group 1216 should be analyzed as a starting point for developing Funding period 2011 – 2015 antivirals. Funded by Leibniz Graduate School for Emerging Title Nipah virus replication in bronchial epithelial Infectious Diseases (EIDIS) cells from pigs and humans. Funding period 2012 – 2015 Principal investigator(s) A. Maisner & L. Sauerhering Summary To answer the question why respiratory Title Characterization of matrix protein-mediated infections caused by highly pathogenic Nipah viruses assembly of highly pathogenic Nipah viruses using a (NiV) are generally observed in pigs but rarely seen virus-like particle (NiVLP) system. in humans, this project compares the influence of Principal investigator(s) A. Maisner & M. Ringel NiV infection on cellular junction markers and Summary To study the role of the Nipah virus matrix cytokine production in primary bronchial epithelial protein during assembly in the absence of infectious cells from pigs and humans at different times p.i. virus replication, a virus-like particle (VLP) system Funded by Manchot-Foundation with a minigenome encoding a reporter plasmid Funding period 2011-2013 (luciferase, eGFP) should be established by coexpressing plasmid-expressed wildtype and Title Functional characterization of newly identified mutant viral proteins. African Henipaviruses Funded by Manchot-Foundation Principal investigator(s) A. Maisner & M. Weis Funding period 2014 – 2015 Summary In recent years, novel Henipavirus-related sequences have been identified in bats in Africa. To Title Nipah virus replication in respiratory epithelial evaluate the potential of cross-species infections of cells: Influence of host factors and virus-strain humans or livestock, biological functions of the new specific sequence variations African Henipavirus glycoproteins are studied by Principal investigator(s) A. Maisner, L. Sauerhering & quantitative binding, cleavage or fusion assays, and M. Zickler by infection competition studies in primary porcine Summary To answer the question why respiratory and human cells. infections caused by highly pathogenic Nipah viruses Funded by Manchot-Foundation are generally observed in pigs but rarely seen in Funding period 2012 - 2014 humans, we want to elucidate the molecular requirements (host cell factors, virus variability) Title Role of the endosomal compartment in Nipah deciding on a productive replication in mucosal virus replication surfaces of the respiratory system which critically Principal investigator(s) A. Maisner, S. Erbar & E. influence the pathogenicity and transmissibility of Dietzel Nipah viruses via airway secretions. Summary Activation of the fusion glycoprotein F of Funded by DFG, SFB 1021 (Project B04) – German highly pathogenic Nipah virus (NiV) by endosomal Research Foundation, Collaborative Research Centre host cell proteases is an indispensable prerequisite 1021 for the generation of infectious virus and virus Funding period 2013 – 2016 spread. This project focuses on role of transport sequences within the F cytoplasmic tail for endo- lysosomal trafficking and proteolytic activation by endosomal cathepsins.
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Clinical-theoretical Institutions
Research group Dr. Matrosovich Funded by FluResearchNet, a BMBF-sponsored network dedicated to research on the zoonosis Research projects influenza – Federal Ministry of Education and Title RNA Viruses: the Metabolism of viral RNA, Research Immune Response of the Host Cells, and Viral Funding period 2010 – 2013 Pathogenesis. Project B02: Role of receptor specificity of influenza viruses in host range, cell Title Pathogenesis and transmission of influenza in tropism and pathogenicity pigs (FLUPIG) Principal investigator(s) M. Matrosovich Principal investigator(s) M. Matrosovich Summary The project studies how natural variation Summary The FLUPIG aims at a better understanding of receptor-binding specificity, membrane-fusion of the role of pigs in influenza pandemics. In and sialidase activity of surface glycoproteins of particular, the consortium studies the nature of the influenza viruses affects viral tropism, replication genetic changes that are required for (a) efficient efficiency and pathogenicity in human respiratory replication of an avian virus in pigs, (b) efficient tract. These questions are addressed by using transmission of avian viruses between pigs and (c) recombinant influenza viruses with well-defined virus transmission from pigs to humans and between phenotypic characteristics and primary cultures of humans. human tracheo-bronchial, alveolar and endothelial Funded by EU (7th Framework Programme) cells. The project will improve influenza surveillance Funding period 2010 – 2014 and pandemic preparedness and may lead to the development of new approaches to influenza control Title Influenza virus interactions with receptors and and treatment. inhibitors in human airway epithelium Funded by DFG SFB 1021, Project B02 – German Principal investigator(s) M. Matrosovich Research Foundation, Collaborative Research Centre Summary The EIDIS partners German Primate 1021 Center, Göttingen, and Institute of Virology, Philipps- Funding period 2013 – 2016 University Marburg, jointly investigate emerging infections at the molecular, cellular and organismic Title Role of receptor specificity of influenza viruses level, with a strong focus on highly pathogenic in lung tropism and pathogenicity viruses. In particular, the group headed by M. Principal investigator(s) M. Matrosovich & S.Herold Matrosovich studies mechanisms, by which (JLU-Giessen) hemagglutinin (HA) and neuraminidase (NA) of avian Summary This project studies influenza virus influenza virus limit their replication in the human interactions with receptors in human lung using i) airway epithelium. This is essential for the recombinant influenza viruses with well-defined understanding of receptor-dependent mechanisms receptor-binding specificity and ii) in vivo (mice) and of zoonotic transmission of influenza viruses and in vitro (murine and human) models of infection in barriers that prevent their pandemic spread. alveolar epithelium. The major aim is elucidation of Funded by Leibniz Graduate school for emerging mechanisms of virus-host interactions mediating infectious diseases (EIDIS) viral entry, replication and host innate immune Funding period 2012 – 2015 responses, which ultimately determine pathogenicity Funded by Von Behring-Röntgen-Foundation Title Prediction and prevention of emerging zoonotic Funding period 2010 – 2013 viruses with pandemic potential using multidisciplinary approaches (PREDEMICS) Title Characterization of the neuraminidase of H1N1 Principal investigator(s) M. Matrosovich 2009 swine-origin influenza virus: functional Summary PREDEMICS brings together 23 teams from properties and role in viral host range and 17 institutions in 8 countries with cross-disciplinary pathogenicity expertise in veterinary and human medicine. The Principal investigator(s) M. Matrosovich & V. aim of the project is to unravel the complex Czudai-Matwich interactions between the factors involved in the four Summary The novel pandemic H1N1/09 virus is a stages of emergence, i.e. exposure and introduction reassortant with a unique gene constellation. It is into a new host species, infection causing local thought that acquisition of a novel neuraminidase chains of transmission, spread in human populations gene may have provided the emergent virus and post-transfer adaptation leading to widespread replicative advantage in humans. This project studies transmission and pandemics. The project will focus functional properties of the neuraminidase of on the following zoonotic viruses with epidemic H1N1/09 and tests whether they could have potential in Europe: influenza virus, hepatitis E virus, contributed to enhanced viral replication and viruses of the Japanese encephalitis serocomplex transmission in humans. and lyssaviruses. Funded by EU (7th Framework Programme)
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Clinical-theoretical Institutions
Funding period 2011 - 2016 Funding period 2007 – 2010 & 2010 – 2013 (two funding periods) Title Inactivated vaccine platforms for emerging viruses Title Degradation of the antiviral interferon-effector Principal investigator(s) S.Becker, F.Weber & M. PKR by the virulence factor NSs of Rift Valley fever Matrosovich virus Summary: The project develops a novel vaccine Principal investigator(s) F. Weber platform which is based on recombinant influenza Summary Rift Valley fever virus (RVFV) is responsible virus expressing foreign protective antigen on the for large and recurrent outbreaks among animals surface of viral particle. The main advantages of this and humans in Africa. We previously demonstrated approach are utilization of widely used technology, that the virulence factor NSs induces the specific equipment and logistics of inactivated influenza degradation of the antiviral host protein PKR. The vaccines. For the proof of principle, candidate aim of the present proposal is to elucidate the vaccine against MERS coronavirus is being developed. molecular mechanisms underlying NSs action. Funded by: German Center for Infection Research Funded by DFG, We 2616/5-2 German Research (DZIF), TTU Emerging Infections – Federal Ministry of Foundation Education and Research Funding period 2010 – 2013 Funding period 2013 – 2015 Title Development of new vaccine candidates against CCH fever Principal investigator F. Weber Research group Dr. Strecker Summary To this date, there is no research program on vaccine development for Crimean Congo Hemorrhagic fever virus (CCHFV). The aim of project Research projects is to develop conventional and novel vaccine Title Lassa virus: host cell tropism and molecular candidates like recombinant antigens, DNA pathogenesis constructs, and virus-like particles, and to Principal investigator(s) T. Strecker and S.K. Fehling characterize the immune responses and protective Summary The primary transmission route of Lassa capacity. virus from its rodent host to humans is by direct Funded by EU FP7 (“CCH Fever”) exposure to virus-containing rodent excretions. Funding period 2010 – 2014 Therefore, the respiratory tract represents an important virus entry site. Aim of this project is to Title Disturbance of the nuclear and nucleolar understand how Lassa virus overcomes the epithelial compartments by a viral interferon antagonist barrier and disseminates from the airway epithelium Principal investigator F. Weber to other parts of the body through the blood or Summary We found that the virulence factor NSs of lymphatic system. the La Crosse encephalitis virus acts by degrading Funded by: DGF SFB 1021 TP B05, German Research the host cell RNA polymerase II. The project is Foundation, Collaborative Research Centre 1021 intended to determine the molecular mechanism von Behring-Röntgen-Foundation (interaction partners, signaling pathways, protein Funding period 2013-2016 DGF SFB 1021 domains) 2013 – 2014 von Behring-Röntgen-Foundation Funded by DFG, SFB 593, TP B13 – German Research
Foundation, Collaborative Research Centre 593 Funding period 2011 – 2014 Research group Professor Weber Title Physiological function of the pathogen Research projects recognition receptor RIG-I Title SARS coronavirus and the antiviral interferon Principal investigator(s) F. Weber system Summary RIG-I is an intracellular pathogen sensor Principal investigator(s) F. Weber essential for the recognition of a wide array of Summary Interferons (IFN-alpha/beta) are the only viruses. The activation of RIG-I by viral RNA in licenced drugs against SARS-coronavirus (SARS-CoV). infected cells activates an antiviral IFN response, but We have previously shown SARS-CoV is sensitive to can also result in a storm of pro-inflammatory the antiviral action of IFN, but that infected cells are cytokines. Despite massive efforts by the research unable to secrete IFN. The aims of this project are (i) community, it remains unclear which viral RNA- to identify the viral factor(s) which block IFN containing structures are activating RIG-I. This production, and (iii) to identify the IFN-stimulated project engages the latest tools and methods antiviral factor responsible for inhibiting SARS-CoV. developed by us to solve this question. Funded by BMBF, 01KI0705 – Federal Ministry of Funded by UKGM – University Hospital Giessen and Education and Research Marburg
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Clinical-theoretical Institutions
Funding period 2012 – 2013
Title Recognition of zoonotic viruses by the pathogen sensor RIG-I.
Principal investigator(s) F. Weber Summary This project includes the screening of a large set of zoonotic viruses to determine their RIG-I activating (or -dampening) structures. Funded by Leibniz Graduate School for Emerging Infectious Diseases (EIDIS) Funding period 2012 - 2015
General information about the institute
Research funding 5.658.983,09 €
Most important publications Schudt G, Kolesnikova L, Dolnik O, Sodeik B, Becker S (2013) Live-cell imaging of Marburg virus-infected cells uncovers actin-dependent transport of nucleocapsids over long distances. Proceedings of the National Academy of Sciences of the United States of America 110(35), 14402-14407
Weber M, Gawanbacht A, Habjan M, Rang A, Borner C, Schmidt AM, Veitinger S, Jacob R, Devignot S, Kochs G, Garcia-Sastre A, Weber F (2013) Incoming
RNA virus nucleocapsids containing a 5'- triphosphorylated genome activate RIG-I and antiviral signaling. Cell host & microbe 13(3), 336-346
Czudai-Matwich V, Otte A, Matrosovich M, Gabriel G, Klenk HD (2014) PB2 mutations D701N and S714R promote adaptation of an influenza H5N1 virus to a mammalian host. Journal of virology 88(16), 8735- 8742
Dolnik O, Kolesnikova L, Welsch S, Strecker T, Schudt, G, Becker S (2014) Interaction with Tsg101 is necessary for the efficient transport and release of nucleocapsids in marburg virus-infected cells. PLoS pathogens 10(10), e1004463
Peitsch C, Klenk HD, Garten W, Bottcher- Friebertshauser E (2014) Activation of influenza A viruses by host proteases from swine airway epithelium. Journal of virology 88(1), 282-291
Contact Details: Hans-Meerwein-Str. 2, 35043 Marburg, Tel.:++49 (0) 6421-28 66254 Director: Professor Dr. Stephan Becker
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Centre for Human Genetics
Research Groups Professor Bohlander Title Molecular genetical and functional analysis of (till October 2013) ichtyoses caused by genetic defects in cholesterol Professor Grzeschik (emeritus) biosynthesis Principal investigator K.-H. Grzeschik Provisional Direction PD Dr. Fritz Summary CHILD-syndrome and Conradi-Hünermann- Happle-syndrome (CDPX2) are caused by deficiency Main fields of research in two successive steps of the cholesterol synthesis Human genetics, dermatogenetics (Prof. pathway. The project aimed at detecting mutated Grzeschik) sites in the underlying genes and characterizing Human genetics, leukemia genetics (Prof. functionally their effect on the proteins NSDHL and Bohlander) EBP, respectively. Funded by BMBF – Federal Ministry of Education Research projects and Research, DLR 01GM0903 Title Identifizierung von genomischen, Funding period 2009 – 2013 epigenomischen und proteomischen Zielen des CALM/AF10 Fusionsproteins Principal investigator S. Bohlander Summary This project seeks to elucidate the General information about the institute genomic targets (direct binding sites) of the CALM/AF10 fusion protein and tries to identify Research funding 21.801,15 € epigenetic changes mediated by the expression of CALM/AF10. Furthermore, we study the interaction network of CALM/AF10 with other proteins using a Most important publications yeast-two hybrid screening approach. In addition, Diffner E, Beck D, Gudgin E, … , Bohlander SK, Buske the infrastructure for the bioinformatics analysis of C, Burnett A, Ottersbach K, Vassiliou GS, Olivier J, large of gene expression datasets and their Wong JW, Göttgens B, Huntly BJ, Pimanda JE (2013) correlation with clinical outcome in AML and CLL was Activity of a heptad of transcription factors is established. associated with stem cell programs and clinical Funded by BMBF – Federal Ministry of Education outcome in acute myeloid leukemia. Blood and Research (Nationales Genomforschungs- 121:2289-2300 netzwerk, NGFN) Funding period 2002 – 2013 Li Z, Herold T, He C,…,, Bohlander SK, Chen J (2013) Identification of a 24-Gene prognostic signature that Title The role of TET proteins in myeloid neoplasia improves the European leukemia net risk Principal investigators S. Bohlander, K. Spiekermann classification of acute myeloic leukemia. J Clin Oncol & H. Leonhardt 31:1172-1181 Summary The TET (ten eleven translocation) proteins are oxygenases that convert 5 Meyer C, Hofmann J, Burmeister T, Kakadia PM, methylcytosine (5MC) into 5 hydroxymethylcytosine Bohlander SK, Ahlmann M, Choi JR, Gameiro P et al. (5HMC). Mutations affecting TET2 and translocations (2013) The MLL recombinome of acute leukemias in resulting in an MLL/TET1 fusion protein are found in 2013. Leukemia 27:2165-2176 various types of myeloid leukemias. It is the aim of this project to study the correlation between TET2 Malik S, Percin FE, Bornholdt D, Albrecht B, mutations, TET2 expression levels, 5HMC levels and Percesepe A, Koch MC, Landi A, Fritz B, Khan R, global gene expression level changes in myeloid Mumtaz S, Akarsu NA, Grzeschik KH (2014) neoplasms. In addition, we are establishing an Mutations affecting the BHLHA9 DNA-binding MLL/TET1 murine bone marrow transplantation domain cause MSSD, mesoaxial synostotic model to investigate the transforming potential of syndactyly with phalangeal reduction, Malik-Percin this fusion protein and its effect on 5MC and 5HMC type. Am J Hum Genet 95(6):649-659 levels. Funded by DFG German Science Foundation, Priority Programme 1463 Contact Details: Funding period 2011 – 2013 Bahnhofstrasse 7, 35033 Marburg Tel.:++49 (0) 6421-28 66233 Provisional Direction: PD Dr. Barbara Fritz
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Institute of Pathology
Research Group Professor R. Moll Title Tissue-based pathological analyses Principal investigator(s) R. Moll Main fields of research Summary The central pathology service project Z04 The central research topics of the institute cover was responsible for tissue-based morphological specific aspects of cell and tumor biology. A main investigations for the SFB Transregio 17 and its research focus is related to the cytoskeleton and scientific projects. These comprised histological and cellular adhesion mediated by desmosomes. As an immunohistochemical analyses of human and important component of desmosomal architecture experimental animal tissues, tissue microarrays, and function we are analyzing the regulation on morphometry, and characterization of antibodies on transcriptional and post-translational level of paraffin-embedded tissues. plakophilin 3 (PKP3), an affiliate of the eponymous Funded by DFG, SFB TR 17 – German Research protein family. PKPs may also be involved in further Foundation, Transregional Collaborative Research cellular processes such as translational regulation, Centre 17 cellular stress response, malignant transformation Funding period 2008 – 2013 and invasion of cells. Moreover, our institute served as a core facility on SFB Transregio 17 providing immunohistochemical staining and pathological General information about the institute evaluation of human and murine tissue samples. Histopathological and immunohistochemical services Research funding 107.695,47 € are granted as well for many scientific and clinical studies in collaboration with other departments of the Medical Faculty. The fetal pathology team correlates fetal malformations with genetic Most important publications syndromes. Bommert KS, Effenberger M, Leich E, Küspert M, Murphy D, Langer C, Moll R, Janz S, Mottok A, Research projects Weissbach S, Rosenwald A, Bargou R, Bommert K Title Expression, posttranslational modifications and (2013) The feed-forward loop between YB-1 and subcellular distribution of plakophilins: Significance MYC is essential for multiple myeloma cell survival. in epithelial tumors Leukemia 27:441-50 Principal investigator(s) A. Schmidt & R. Moll Summary We identified a new protein variant of the Makarova G, Bette M, Schmidt A, Jacob R, Cai C, human PKP3 gene - PKP3b - that is transcriptionally Rodepeter F, Betz T, Sitterberg J, Bakowsky U, Moll regulated by an independent promoter element and R, Neff A, Sesterhenn A, Teymoortash A, Ocker M, exhibits a restricted expression pattern in normal Werner JA, Mandic R (2013) Epidermal growth and transformed tissues compared to the regular factor-induced modulation of cytokeratin expression variant PKP3a. Additionally, we analyzed a specific levels influences the morphological phenotype of modification of PKP3 (phosphorylation of tyrosine- head and neck squamous cell carcinoma cells. Cell 195) for its functional relevance in normal and Tissue Res 351:59-72 malignant cells. We identified proto-oncogenic Src- kinase as one relevant enzyme catalyzing this Schoner K, Kohlhase J, Müller AM, Schramm T, modification and could show that this also takes Plassmann M, Schmitz R, Neesen J, Wieacker P, place after epidermal growth factor receptor (EGFR) Rehder H (2013) Hydrocephalus, agenesis of the stimulation as a downstream event. This corpus callosum, and cleft lip/palate represent phosphorylation seems to be associated with a frequent associations in fetuses with Peters' plus change of functional properties of PKP3. We could syndrome and B3GALTL mutations. Fetal PPS identify this modification also in some tumor entities phenotypes, expanded by Dandy Walker cyst and such as poorly differentiated prostate cancer. Finally encephalocele. Prenat Diagn 33:75-80 we are analyzing newly discovered interacting proteins with PKP3 identified during a two-hybrid Bergs JW, Neuendorff N, van der Heijden G, screen on immunobiochemical and cell biological Wassenaar E, Rexin P, Elsässer HP, Moll R, Baarends level in various diploma, bachelor or master theses. WM, Brehm A (2014) Differential expression and sex Funded by Deutsche Krebshilfe – German Cancer Aid chromosome association of CHD3/4 and CHD5 Funding period 2009 – 2013 during spermatogenesis. PLoS One 9(5):e98203
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Mühmer M, Ditthardt D, Jäkel J, Wischmann V, Moll R, Schmidt A (2014) An alternative promoter of the human plakophilin-3 gene controls the expression of the new isoform PKP3b. Cell Tissue Res 355:143-162
Neuber S, Jäger S, Meyer M, Wischmann V, Koch PJ, Moll R, Schmidt A (2014) c-Src mediated tyrosine phosphorylation of plakophilin 3 as a new mechanism to control desmosome composition in cells exposed to oxidative stress. Cell Tissue Res Epub 2014 Dec 12
Contact Details: Baldingerstr., 35043 Marburg, Tel.:++49 (0) 6421-58 62270 Director: Professor Dr. Roland Moll
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Division of Neuropathology
Research Group Professor Pagenstecher Title Role of IRF9 in the infection of mice with Lymphocytic choriomeningitis virus (LCMV) Main fields of research Principal investigator(s) M. Hofer & A. Pagenstecher The Department’s main research interest is in the Summary We investigate the effects IRF9-deficiency fields of neuroimmunology and neurooncology. We has on the clinical course and immune response of are interested in the induction of immune reactions mice infected with LCMV. in the central nervous system (CNS) in animal models Funded by DFG – German Research Foundation of inflammation such as experimental allergic Funding period 2010 – 2014 encephalomyelitis, virus and bacterial infection and tumor rejection. Moreover, we investigate the Title Presence of persistent virus infections in the factors that render astrocytes tumorigenic and lead human CNS to the infiltrative behaviour of these cells in the CNS. Principal investigator(s) M. Hofer & A. Pagenstecher Main factors we are interested in are Matrix Summary We aim to determine the presence of Metalloproteases and their inhibitors (MMPs, virus nucleic acid and protein in the non-inflamed ADAMs and TIMPs), IRF-9 and IL-12. human CNS. Funded by Kooperationsvertrag Research projects Funding period 2011 – 2012 Title Inititation of immune responses in the CNS Principal investigator(s) A. Pagenstecher Summary We investigate whether it is possible to induce a specific immune reaction against MOG General information about the institute peptide in the CNS of mice deficient for IL-12 and IL23 that express IL-12 exclusively in the CNS under Research Funding 76.125,00 € control of the GFAP promoter.
Title Effect of MT-MMPs in the infiltrative behaviour Most important publications of astrocytes and glioma cells Stellzig J, Chariot A, Shostak K, Ismail Göktuna S, Principal investigator(s) A. Pagenstecher Renner F, Acker T, Pagenstecher A, Schmitz ML. Summary Astrocytic tumors diffusely invade the (2013) Deregulated expression of TANK in surrounding brain. It is not fully understood which factors mediate this propensity. We have developed glioblastomas triggers pro-tumorigenic ERK1/2 and a new in vitro model that allows for the AKT signaling pathways. Oncogenesis: 2:e79 determination of the influence of single proteases for the infiltrative behaviour of astrocytes in the El Hindy N, Keyvani K, Pagenstecher A, Dammann P, CNS. Sandalcioglu IE, Sure U, Zhu Y (2013) Implications of
Dll4-Notch signaling activation in primary Title Effect of TIMP-1 expression in cerebral ischemia Principal investigator(s) A. Pagenstecher glioblastoma multiforme. Neuro Oncol 15(10):1366- Summary Tissue inhibitor of MMPs 1 (TIMP-1) has 78 been shown to be neuroprotective on hypoxic neurons. In this project we determine in vivo and in Timofeev O, Schlereth K, Wanzel M, Braun A, vitro the effect of transgenic expression of TIMP-1 in Nieswandt B, Pagenstecher A, Rosenwald A, Elsässer the CNS in the course of cerebral ischemia following HP, Stiewe T (2013) p53 DNA Binding Cooperativity Is medial cerebral artery occlusion (MCAO). Essential for Apoptosis and Tumor Suppression In Vivo. Cell Rep 3(5):1512-25 Title Tumorigenicity of myc and Akt in astrocytes Principal investigator(s) A. Pagerstecher Radke J, Bortolussi G, Pagenstecher A (2013) Summary In order to establish an animal model for Activated Akt and c-Myc induce a progenitor-like glioma we transduce primary murine astrocytes with phenotype of mature primary p53-/- astrocytes and myc, Akt or both oncogenes and investigate the render these cells gliomagenic in the brain of growth behaviour, phenotype and tumorigenicity of immunocompetent mice. PLoS One 8:e56691 these cells.
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Clinical-theoretical Institutions
Huber M, Heink S, Pagenstecher A, Reinhard K, Ritter J, Visekruna A, Guralnik A, Bollig N, Jeltsch K, Heinemann C, Wittmann E, Buch T, Prazeres O, Brüstle A, Brenner D, Mak TW, Mittrücker HW, Tackenberg B, Kamradt T, Lohoff M. (2013) Pathogenic IL-17A-dependent help of Tc17 cells for Th17-mediated autoimmune encephalomyelitis. J Clin Invest 123(1):247-60
Teymoortash A, Zieger L, Hoch S, Pagenstecher A, Hofer MJ (2014) Distinct microscopic features of perineural invasion in adenoid cystic carcinoma of the head and neck. Histopathology 64:1037-9
Contact Details: Baldingerstr., 35043 Marburg, Tel.:++49 (0) 6421-58 62282 Director: Professor Dr. Axel Pagenstecher
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Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics
Professor H. Renz Title The role of viral influenza infection on the PD Dr. H. Garn, PD Dr. Dr. P. Pfefferle, PD Dr. protection and exacerbation of acute and chronic A. Nockher, PD Dr. T. Stief, PD Dr. N. Al-Fakhri allergic airway inflammation Principal investigator(s) H. Renz
Summary Viral infections have been shown to may Main fields of research exert opposing effects on the development of Major topic of research is the investigation of allergies and asthma depending on virus type, dose, mechanisms of disease development, prevention and time point of infection leading either to allergy and therapy of chronic inflammatory diseases, protection or to disease progression and mainly allergic diseases of the lung. Therefore, exacerbations. Vice versa, allergic inflammation several animal models are developed that mimic within the lung may interfere with immune characteristic features and phenotypes of acute and responses to viruses and viral infections. Thus, chronic allergic airway inflammation. Additionally, interrelationship of these conditions is investigated investigations are extended to the participation in in this project. respective human cohort studies. A newly Funded by DFG, SFB 1021, TP C04 – German established lipidomics platform investigates fatty Research Foundation, Collaborative Research Centre acid patterns during the course of inflammatory 1021 processes. Further projects focus on the role Funding period 2013 – 2016 neurotrophins on lung remodeling, angiogenesis and tumor development, role of endothelium in Title Role of microRNA in the pathogenesis of atherosclerosis and development of novel analytical bronchial asthma systems for clotting cascade parameters. Principal investigator(s) H. Renz in cooperation with T. Braun , Bad Nauheim Research projects Summary MicroRNAs are small non-coding RNA Title Epigenetic regulation of pre- and neonatal molecules regulating gene expression on the post- programming of allergic asthma transcriptional level. Their controlled expression is Principal investigator(s) H. Renz, P. Pfefferle mandatory for normal immune function and an Summary Based on the results of the preceding imbalance in microRNA expression is sufficient to project it is hypothetized that epigenetic regulation cause disease. By studying distinct immune cell mechanisms are involved in the prenatal allergy subsets and structural cells, we intend to identify protection by Acinetobacter lwoffii F78. This project specific microRNAs contributing to asthma investigates in detail DNA methylation and histon pathology. modification processes within candidate genes Funded by von Behring Röntgen Foundation involved in the regulation of allergic immune Funding period 2010 – 2013 responses and their importance for allergy protection. Title Role of Th1 lymphocytes and the transcription Funded by DFG, SFB/TR22, TPA18 – German Science factor Tbet for chronic inflammation initiation Foundation, Transregional Collaborative Research Centre 22 and/or maintenance in a COPD animal model Funding period 2013 – 2014 Principal investigator(s) H. Garn in cooperation with N. Weißmann, JLU Giessen Title Animal models for endotypes of allergic airway Summary It is postulated that Th1-driven inflammation autoimmune processes may contribute to the Principal investigator(s) H. Garn development of chronic obstructive pulmonary Summary This project is the continuation of the disease (COPD). The project investigates the role Th1 animal core facility of the SFB. It extends the line of lymphocytes and their major transcription factor animal models of inflammatory diseases of the lung Tbet on initiation and development of chronic by implementing models of non-eosinophilic airway inflammation in a mouse smoke exposure model to inflammation. In addition, processes of disease evaluate the potential of Tbet as therapeutic target. chronification and their resolution are studied in Funded by LOEWE Centre, UGMLC P9 different asthma phenotype models in comparison. Funding period 2013 – 2014 Funded by DFG, SFB/TR22, TPA18 – German Science Foundation, Transregional Collaborative Research Title FP 7 – PreDicta Centre 22 Principal investigator(s) H. Renz Funding period 2013 – 2014
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Clinical-theoretical Institutions
Summary Development of a DNAzyme specific to infarction to analyze effects on endothelial human RV, analysis of antiviral effectiveness in vitro protection and on stroke. and in vivo, testing of DNAzymes for therapeutic Funded by Hans und Gertie Fischer Foundation potential in a murine RV model of asthma. The team Funding period 2012 – 2013 will also participate in WP2 for the investigation of the role of the lung epithelial barrier in the interplay Title The role of Factor VII activating protease (FSAP) between RV infection and asthma. in the pathogenesis of stroke Funded by EU FP7, PreDicta WP8 – European Union Principal investigator(s) N. Al-Fakhri in cooperation Funding period 2010 – 2015 with S. Kanse and T. Gerriets, JLU Giessen Summary The role of factor VII activating protease Title DZL Disease area AA (FSAP), a circulating protease involved in the Principal investigator(s) H. Renz, H. Garn, P. coagulation and fibrinolysis pathways, in stroke is Pfefferle, A. Nockher investigated in an animal model. Summary Multiplex cytokine, epigenetic and Funded by von Behring Röntgen Foundation lipidomics analyses of samples from children and Funding period 2011 – 2013 adult patients cohorts within the German Lung Center (DZL). Development and characterization of animal models of endophenotypes of asthma and analysis of underlying pathomechanisms. General information about the institute Funded by DZL, BMBF – German Ministry of
Education and Research Funding period 2013 – 2015 Research funding 2.207.094,61 €
Title DZL Disease area CF Principal investigator(s) H. Garn in cooperation with Most important publications M. Mall, University Heidelberg Turowska A, Librizzi D, Baumgartl N, Kuhlmann J, Summary Generation of DNAzymes against the Dicke T, Merkel O, Homburg U, Höffken H, Renz H, epidermal natrium chanel (ENaC) family members as Garn H (2013) Biodistribution of the GATA-3-specific potential therapeutics for the treatment of CF. DNAzyme hgd40 after inhalative exposure in mice, Characterization of these molecules in vitro using rats and dogs. Toxicol Appl Pharmacol 272(2):365-72 primary epithelial cell cultures and in vivo in cooperation with Heidelberg colleagues. Garn H, Neves JF, Blumberg RS, Renz H (2013) Effect Funded by DZL, BMBF – German Ministry of of barrier microbes on organ-based inflammation. J Education and Research Allergy Clin Immunol 131(6):1465-78 Funding period 2013 – 2015 Harb H, van Tol EA, Heine H, Braaksma M, Gross G, Title Plasmatic thrombin activity Overkamp K, Hennen M, Alrifai M, Conrad ML, Renz Principal investigator(s) T. Stief H, Garn H (2013) Neonatal supplementation of Summary Thrombin - Tests measuring thrombin in processed supernatant from Lactobacillus IU/ml instead of clotting seconds are much more rhamnosus GG improves allergic airway refined than the usual clinical blunted assays. These inflammation in mice later in life. Clin Exp Allergy new tests detect without problems even thrombin 43(3):353-64 activities in the clinically so important 1-10 milli- IU/ml range and allow the early diagnosis of Hagner S, Harb H, Zhao M, Stein K, Holst O, Ege MJ, NICPIC changes. The trick consists in using the Mayer M, Matthes J, Bauer J, von Mutius E, Renz H, substrate in the approx. 1fold Km range together Heine H, Pfefferle PI, Garn H (2013) Farm-derived with supramolar arginine concentrations. Gram-positive bacterium Staphylococcus sciuri Funded by Industry, Fellowships W620 prevents asthma phenotype in HDM- and Funding period 2009 – 2014 OVA-exposed mice. Allergy 68(3):322-9
Title Investigation of the protective effects of Pfefferle PI, Weber J, von Mutius E (2013) PASTURE vascular endothelial growth factor (VEGF) on the Study Group. Atopic sensitization in the first year of endothelium through regulation of poly-[ADP- life. J Allergy Clin Immunol 131(3):781-8 ribose]-polymerase (PARP) in the animal model Principal investigator(s) N. Al-Fakhri in cooperation Pfefferle PI, Prescott SL, Kopp M (2013) Microbial with T. Gerriets, JLU Giessen influence on tolerance and opportunities for Summary The pharmacological modulation of the intervention with prebiotics/probiotics and bacterial VEGF system and of PARP through inhibitors and lysates. J Allergy Clin Immunol 131(6):1453-63 small molecules are tested in a rat model of cerebral
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Clinical-theoretical Institutions
Pfefferle PI, Renz H (2014) The mucosal microbiome in shaping health and disease. F1000Prime Rep 6:11
Alrifai M, Marsh LM, Dicke T, Kılıç A, Conrad ML, Renz H, Garn H (2014) Compartmental and temporal dynamics of chronic inflammation and airway remodelling in a chronic asthma mouse model. PLoS One 9(1):e85839
Contact Details: Baldingerstr., 35043 Marburg, Tel.:++49 (0) 6421-58 66235 Director: Professor Dr. Harald Renz
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Clinical-theoretical Institutions
Institute for Lung Research
Research Group Professor B. T. Schmeck 1673 “Functional and Molecular Epidemiology Berlin-Hyderabad”) Main fields of research Funding period 2010 – 2014
chromatin modifications and microRNA Title Regulation of pulmonary inflammation with the regulating lung immunology help of new therapeutical agents Systems biology of lung diseases Principal investigators B. T. Schmeck & S. translational and clinical research (clinical Hippenstiel (Charité Universitätsmedizin Berlin) studies: PhenoCOPD) Summary In animal and cell culture models, the anti- inflammatory and vasoprotective potential of new Research projects experimental COPD-drugs is evaluated. Title microRNA-regulation in pulmonary Funded by Boehringer Ingelheim inflammation (with L. pneumophila) Funding period 2010 -2014 Principal investigators B. T. Schmeck & M. Vingron (Max-Planck-Institute for Molecular Genetics Berlin) Title PneumiR Summary Using the example of infection with Principal investigators B. T. Schmeck & K. Meyer Legionella pneumophila in human cell and tissue (JLU Giessen) cultures as well as in mouse models, the relevance of Summary Infections and neoplasia of the respiratory small, non-protein coding RNAs from host and tract and lung tissue are among of the most frequent pathogen are analysed experimentally (e.g. Deep causes of death worldwide and cause high socio- Sequencing) and bioinformatically modeled with economic burdens. They pose a diagnostic and Systems biological / mathematical methods. urgent challenge. The simple accessibility of Funded by DFG SFB/TR84 (German Research exhalation air is a unique opportunity for non- Foundation – Transregional Collaborative Research invasive diagnosis with high compartment specificity. Center 84) The analysis of exhaled air is both possible in Funding period 2014 - 2018 (second funding period) children and patients who are critically ill. Own previous work show that in exhaled air, RNA is Title Epigenetic regulation of Influenza virus and S. present in sufficient amount and quality so that pneumonia infection miRNA can be detected. Therefore, the aim of the Principal investigators B. T. Schmeck & A. Hocke, project is to look for the small RNAs in exhaled air (Charité Universitätsmedizin Berlin) condensate from patients with infections and Summary The process of respiratory infection can be malignancies of the respiratory tract and to validate affected by different predisposing factors. The them as biomarkers. impact of epigenetic regulations for post-influenza Funded by Collaborative project UKGM - University pneumonia (elicited by S. pneumoniae) is analysed Hospital Giessen and Marburg among others with high-throughput and bio- Funding period 2012 – 2014 informatical methods in human cell and tissue culture. Title DZL-Sysbio-Plattform Funded by BMBF-Progress - Federal Ministry of Principal investigator(s) B. T. Schmeck Education and Research – Summary The aim of the project is to investigate the Funding period 2010 – 2013 role of miRNA regulation in signalling and gene regulatory networks related to lung inflammation Title microRNA as a biomarker for pulmonary using an iterative approach of mathematical inflammation and infection modelling, bioinformatics, and laboratory Principal investigators B. T. Schmeck & S. experiments. The project is to detect critical miRNAs Hippenstiel (Charité Universitätsmedizin Berlin) for lung inflammation in pathological conditions Summary microRNA bears an important meaning for associated to infection and cancer. Other objectives the differentiation and regulation of monocytic cells. of the project are the development of bioinformatics In blood monocytes from patients with acute and methods for analysis and construction of miRNA chronic pulmonary infections in Germany and India, related biochemical networks. expression and mutations of microRNA are analysed Funded by BMBF – Federal Ministry of Education as potential biomarkers. and Research Funded by DFG-GRK 1673 (German Research Funding period 2011 – 2015 Foundation – International Research Training Group
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Clinical-theoretical Institutions
Title Systems biology of pulmonary inflammation histone acetylation and their predicted targeting Principal investigator B. T. Schmeck miRNAs. As an outlook, promising synthetic miRs will Summary COPD, asthma and pneumonia are be studied in vivo. characterized by significantly different types of Funded by Collaborative project UGMLC – LOEWE inflammation. A very important role of chromatin Centre Universities of Giessen and Marburg Lung modification within the process of inflammation Center (UGLMC) could be demonstrated in own investigations. The Funding period 2013 – 2014 regulation of these different kinds of inflammation is analysed experimentally (ChIP-Seq) and bio- Title Molecular characterization of macrophage informatically and modeled with Systems biological / phenotypes in pneumonia and asthma mathematical methods. Principal investigators B. T. Schmeck, H. Garn, A. Funded by BMBF Forsys Partner Federal Ministry of Sittka & S. Herold Education and Research Summary The aim of this study is to test the Funding period 2008 – 2013 hypothesis, that chromatin-status and miRNA- patterns are important regulators of macrophage Title microRNA at the crossroad of lung polarization in different pulmonary disease settings. inflammation, regeneration and cancer (miRSys) In detail, we will determine the genome-wide Principal investigators B. T. Schmeck & J. Vera- acetylation state of histone H4, and a Gonzalez (Friedrich-Alexander-Universität Erlangen- comprehensive miRNA and mRNA pattern in a) Nürnberg) human macrophages, differentiated and polarized Summary Aim of this project is to understand the from PBMCs, b) human alveolar macrophages from role of miRNA in the pathophysiological BAL, c) exudate macrophages from a mouse model development of inflammation, regeneration and of gram-negative pneumonia, and d) lung carcinogenesis in the lung. The basis is to develop a macrophages from a mouse model of allergic asthma. mathematical model that is supplemented with A comprehensive bioinformatics approach will be quantitative data in iterative cycles by modelling and applied to cluster the results with respect to experimental series. Afterwards, hypotheses different macrophage subtypes, and mRNA changes concerning the structure of the model and the will be correlated with corresponding histone supposed role of feedback loops are integrated and acetylation and their predicted targeting miRNAs. tested by computer simulations. The results of these Putative interaction partners will be validated and simulations are used to validate hypotheses about phenotypically characterized in vitro. As an outlook, the miRNA-regulation in inflammation reactions in promising synthetic miRs will be studied in vivo. the lung. It will also be possible to predict the Funded by Collaborative project UGMLC – LOEWE behaviour of the system in the complex biological Centre Universities of Giessen and Marburg Lung context of lung inflammation. Center (UGLMC) Funded by BMBF Innovationswettbewerb System- Funding period 2013 – 2014 biologie - Federal Ministry of Education and Research Title Experimental modelling and validation of Funding period 2013 – 2015 pneumonia pathophysiology Principal investigators B. T. Schmeck & M. Title Molecular regulation of iNOS in experimental Witzenrath, (Charité Universitätsmedizin Berlin) and clinical emphysema Summary Mathematical modelling on the basis of Principal investigator B. T. Schmeck deeply phenotyped clinical cohorts is the central Summary In this project, the hypothesis that systems medicine approach in CAPSyS. This chromatin-status and miRNA-patterns are important approach has to be complemented by goal-directed regulators of (1) iNOS expression and (2) the cutting edge in vivo and in vitro experiments, subsequent development of emphysema and because (1) important features of pneumonia vascular remodeling in cigarette smoke induced lung pathogenesis evade clinical observation as they disease. A comprehensive miRNA and mRNA pattern happen too early, or are inaccessible in the required will be determined, and chromatin modifications at timely and spatial resolution in patients, and (2) smoke-regulated genes in alveolar epithelial cells, concise model construction and validation requires endothelial cells and vascular smooth muscle cells at manipulation of biological pathways, which is different time points in our murine model of chronic impossible in patients. cigarette smoke exposure. Subsequent, knock-out This subproject uses experimental models to focus and L-NIL treated mice will be analyzed. A on two aims: Central aspects of pneumonia comprehensive bioinformatics approach will be pathology inaccessible to patient-centred research applied to cluster the results with respect to will be elucidated in highly standardized and well emphysema and vascular remodeling, and mRNA controlled experimental models in vitro, ex vivo and changes will be correlated with corresponding in vivo, to provide homogenous data as starting
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Clinical-theoretical Institutions points for mathematical modelling of model of post-influenza pneumococcal pneumonia pathophysiologic sequences. Important functional and the analysis of exosomes from bronchoalveolar modules and hypotheses established from previous lavage. The translational potential of this project studies and the patient-centred part will be includes the identification of possible biomarkers for narrowed down by hypothesis-driven in vitro severe course of the disease. screening approaches, and analysed in depth by a Funded by DFG-SFB/TRR84 (internal competition) process including model construction, optimization, Funding period: 2014 and validation iterating between wet lab and mathematics.
Funded by BMBF CapSys – Federal Ministry of Education and Research Funding period 2014 – 2017 General information about the institute
Title Extracellular Ribonuclease1: A new protective Research Funding 1.336.742,95 € factor for vascular diseases Principal investigators B. T. Schmeck & K. T. Preissner (JLU Giessen) Summary Recently, vascular Ribonuklease1 (RNase1) Most important publications was characterized as a new, vessel-protective protein. It neutralizes or prohibits the procoagulant, Chillappagari S, Venkatesan S, Garapati V, oedema-promoting or hyper-inflammatory activities Mahavadi P, Munder A, Seubert A, Sarode G, of extra-cellular RNA (eRNA) within the vessel Guenther A, Schmeck BT, Tümmler B, Henke MO system. In this project, regulatory mechanisms of (2014) Impaired TLR4 and HIF expression in cystic RNase-expression and –secretion as well as its fibrosis bronchial epithelial cells downregulates protective role in vessel diseases will be determined hemeoxygenase-1 and alters iron homeostasis in and further validated in animal models. In addition, vitro. Am J Physiol Lung Cell Mol Physiol 307:L791- in patient cohorts, we will investigate whether an 9. RNase1-deficiency or –mutant can be presumed as a risk factor for the development of von Deetzen MC, Schmeck BT, Gruber AD, hyperinflammatory or thrombotic diseases. Klopfleisch R (2014) Malignancy Associated Funded by von Behring-Röntgen Foundation MicroRNA Expression Changes in Canine Mammary Funding period 2014 – 2016 Cancer of Different Malignancies. ISRN Vet Sci
148597 Title The influence of the virulence factor pneumolysin on histone modifications in Greulich T, Nell C, Koepke J, Fechtel J, Franke M, pneumococcal pneumonia Schmeck B, Haid D, Apelt S, Filipovic S, Kenn K, Principal investigator K. Seidel Janciauskiene S, Vogelmeier C, Koczulla AR (2014) Summary Pneumococcal pneumonia belongs to the Benefits of whole body vibration training in patients leading causes of death worldwide. Its course is hospitalised for COPD exacerbations - a randomized mainly determined by virulence factors of the clinical trial. BMC Pulm Med 14:60 bacterium Streptococcus pneumoniae (S. pneumoniae) and the immune response of the host, Kirsch S, Schrezenmeier E, Klare S, Zaade D, Seidel K, emerging from the bronchial epithelium of the lung. Schmitz J, Bernhard S, Lauer D, Slack M, Goldin-Lang In animal models of severe infections, „epigenetic“ P, Unger T, Zollmann FS, Funke-Kaiser (2014) The therapeutical strategies have been studied (pro)renin receptor mediates constitutive PLZF- successfully. The aim of the proposed project is independent pro-proliferative effects which are providing the scientific basis for better inhibited by bafilomycin but not genistein. Int J Mol understanding of such therapy. Therefore histone Med 33:795-808 modifications within pneumococcal infection, its underlying mechanisms and impacts is to Smirnova L, Block K, Sittka A, Oelgeschläger M, Seiler investigate. AE, Luch A (2014) MicroRNA profiling as tool for in Funded by P. E. Kempkes Foundation vitro developmental neurotoxicity testing: the case Funding period 2014 – 2015 of sodium valproate. PLoS One 9(6):e98892
Title The role of miRNA in the pathogenesis of post- influenza pneumococcal pneumonia Principal Haag T, Herkt CE, Walesch SK, Richter AM, investigator Evelyn Vollmeister Dammann RH (2014) The apoptosis associated Summary This project addresses the relevant clinical tyrosine kinase gene is frequently hypermethylated problem of post-influenza pneumonia with a mouse
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Clinical-theoretical Institutions in human cancer and is regulated by epigenetic mechanisms. Genes Cancer 5(9-10):365-74.
Kastl A, Dieckmann S, Wähler K, Völker T, Kastl L, Merkel AL, Vultur A, Shannan B, Harms K, Ocker M,
Parak WJ, Herlyn M, Meggers E (2013) Rhenium complexes with visible-light-induced anticancer activity. ChemMedChem 8(6):924-7.
Namsolleck P, Boato F, Schwengel K, Paulis L, Matho
KS, Geurts N, Thöne-Reineke C, Lucht K, Seidel K,
Hallberg A, Dahlöf B, Unger T, Hendrix S, Steckelings
UM (2013) AT2-receptor stimulation enhances axonal plasticity after spinal cord injury by upregulating BDNF expression. Neurobiol Dis 51:177-
91.
Sittka A, Schmeck B (2013) MicroRNAs in the lung.
Adv Exp Med Biol 774:121-34
Sittka A, Vera J, Lai X, Schmeck BT (2013) Asthma phenotyping, therapy, and prevention: what can we learn from systems biology? Pediatr Res 73(4 Pt
2):543-52
Zaade D, Schmitz J, Benke E, Klare S, Seidel K, Kirsch
S, Goldin-Lang P, Zollmann FS, Unger T, Funke-Kaiser
H (2013) Distinct signal transduction pathways downstream of the (P)RR revealed by microarray and
ChIP-chip analyses. PLoS One 8:e57674
Zahlten J, Steinicke R, Bertrams W, Hocke AC, Scharf
S, Schmeck B, Witzenrath M, Hammerschmidt S,
Suttorp N, Hippenstiel S (2013) TLR9- and Src- dependent expression of Krueppel-like factor 4 controls interleukin-10 expression in pneumonia. Eur
Respir J 41:384-9
Contact Details: BMFZ, Hans-Meerwein-Straße 2, 35043 Marburg Tel.:++49 (0) 6421- 28 21954 Director: Professor Dr. Bernd T. Schmeck
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Clinical Institutions
Department of Anaesthesia and Intensive Care Therapy
Chair Professor H. Wulf Main fields of research Effects on therapeutic induced hypothermia on Main fields of research organ function in an experimental porcine Regional Anaesthesia polytrauma model. Perioperative Patient Safety, outcome and Principal investigator(s) T. Steinfeldt quality of life (including Pain, PONV) Summary Induced moderate hypothermia after cardiac arrest has been proven to be beneficial and Hypothermia (Surgery, Trauma) is established in clinical practice. Therefore, in a Resuscitation porcine model, the effect of hypothermia after a Perioperative Quality of Life combined trauma to head, thorax, liver and lower extremity was investigated regarding pulmonary, Regional Anaesthesia cardiac, cerebral and renal outcome and on systemic Prof. Dr. T. Steinfeldt, Prof. Dr. H. Wulf inflammatory reaction. Funded by Reinfried-Pohl-Stiftung
Main fields of research Safety in regional anesthesia. Experimental and Perioperative Patient Safety clinical models for simulation, detection and Dr. HJ Aust, PD Dr. D. Rüsch, Prof. Dr. L. prevention of nerve injury following several Eberhart, Prof. Dr. H. Wulf intervention as used in daily practice in patients. Topics: nerve localization, needle nerve proximity, nerve injury. Research projects in 2013 and 2014: Main fields of research Selective saphenous nerve block for prevention of Perioperative patient safety ; preoperative anxiety motor weakness for knee arthroplasty. Supraclavicular blocks instead of interscalene block Research projects Preoperative risk evaluation of for shoulder surgery as a prevention of adult patients before elective non-cardiac surgery; diaphragmatic paralysis by local anesthetics. Prevention of postoperative hypoxemia; Preoperative anxiety: incidence, predictors and Title Prevention of side effects during regional manifestations; Coping strategies of preoperative anesthesia anxiety; Postoperative nausea and vomiting (PONV): Principal investigator(s) T. Steinfeldt & H. Hinnerk prophylaxis and treatment of PONV; Influence of Summary Peripheral nerve blocks are of anaesthesia on postoperative sleep patterns, fundamental relevance for postoperative analgesia perioperative hemodynamic monitoring by in the postoperative phase after knee arthroplasty. transthoracic echocardiography. Therefore femoral nerve blocks are commonly Principal investigator(s) H. Aust & D. Rüsch applied. Unfortunately motor weakness in the Summary Hypoxemia in the period right after quadriceps muscle often results due to the femoral surgery under general anesthesia during patient nerve block. Thereby it is suggested, that patients transfer to the recovery room is still a frequent are at risk of unintentional falls and consecutive complication in patients breathing room air. injuries. By selective blocking of the saphenous Therefore, routine monitoring of SpO2 during nerve we intended to prevent a severe motor patient transfer in all patients and supplementary weakness of the quadriceps muscle. Therefore we oxygen if necessary is recommended. compared motor strength and pain quality in 50 Survey on the incidence and manifestations of patients following femoral nerve or saphenous nerve preanesthesia and preoperative anxiety as well as block for knee arthroslasty. coping strategies regarding these anxieties in more Funded by Institutional grant than 3000 patients. Results so far (analysis not entirely completed): Anxiety about surgery is slightly more pronounced Therapeutic hypothermia in polytrauma than anxiety about anesthesia. Most important risk patients during intensive care therapy factors for preoperative anxiety are female gender Prof. Dr. T. Steinfeldt, Prof. Dr. H. Wulf and bad experience with a previous anesthetic. Type of surgery does not have a significant impact on (Cooperation with the Department of Traumatology (Prof. Dr. Ruchholtz) preoperative anxiety. Funded by Medtronic Inc. gave access to subcutaneous sensors, no further funding
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Clinical Institutions
Resuscitation Most important publications Steinfeldt T, Wiesmann T, Nimphius W, Cornelius V, PD Dr. C. Kill, Dr. Dersch, Prof. Dr. H. Wulf Eismann D, Kratz T, Hadzic A, Wulf H, Werner T Title New techniques of combining ventilation and (2014) Perineural hematoma may result in nerve cardiac compression during cardiopulmonary inflammation and myelin damage. Reg Anesth Pain resuscitation Med 39(6):513-9 Summary A synchronized ventilation and compression could have a positive influence on Wiesmann T, Bornträger A, Vassiliou T, Hadzic A, ROSC (re-occurance of spontaneous circulation), Wulf H, Müller HH, Steinfeldt T (2014) Minimal oxygenation, hemodynamics and outcome after current intensity to elicit an evoked motor response cardiopulmonary resuscitation in an experimental cannot discern between needle-nerve contact and porcine model of cardiac arrest. intraneural needle insertion. Anesth Analg 118(3): Funded by Federal Ministry of Economics No 681-6 KF2502403FR0, KF2660001FR0 Aust H, Kranke P, Eberhart LH, Afshari A, Weber F, Brieskorn M, Heine J, Arndt C, Rüsch D (2014) Perioperative Quality of Life Impact of medical training and clinical experience on the assessment of oxygenation and hypoxaemia Prof. Dr. L. Eberhart, T. Koch, Prof. Dr. H. Wulf after general anaesthesia: an observational study. J Clin Monit Comput Epub 2014 Sep 25 Main fields of research The research group “Perioperative quality of life” Aust H, Dinges G, Nardi-Hiebl S, Koch T, Lattermann works on strategies to measure and improve quality R, Schricker T, Eberhart LH (2014) Feasibility and of life of surgical patients in the perioperative precision of subcutaneous continuous glucose period. In this contexts strategies against monitoring in patients undergoing CABG surgery. J postoperative complications like postoperative Cardiothorac Vasc Anesth 28(5):1264-72 nausea and vomiting, pain, shivering, confusion and fatigue are of major concern. Rahe-Meyer N, Fennema H, Schulman S, Klimscha W, Clinical research, epidemiologic studies and meta- Przemeck M, Blobner M, Wulf H, Speek M, McCrary analyses are the methodological cornerstones for Sisk C, Williams-Herman Debora Woo T, Szegedi the group. (2014) Armin Effect of Reversal of Neuromuscular Blockade with Sugammadex versus Usual Care on Title Amisulpirid alone or in combination for the Bleeding Risk in a Randomized Study of Surgical prevention of postoperative nausea and vomiting Patients. Anesthesiology 121:969-77 Amisulpirid for the treatment of breakthrough postoperative nausea and vomiting Dette F, Cassel W, Urban F, Zoremba M, Koehler U, Principal investigator(s) L Eberhart Wulf H, Graf J, Steinfeldt T (2013) Occurrence of Summary The dopamine D2-antagonist droperidol rapid eye movement sleep deprivation after surgery was frequently used to prevent postoperative under regional anesthesia. Anesth Analg 116(4):939- nausea and vomiting until safety concerns limited its 43 use. Amisulpirid, a D2/D3-antagonist has shown promising anti-emetic efficacy at very low doses. The Kill C, Hahn O, Dietz F, Neuhaus C, Schwarz S, drug given IV prior to surgery is safe and highly Mahling R, Wallot P, Jerrentrup A, Steinfeldt T, Wulf effective at reducing PONV in moderate/high-risk H, Dersch W (2014) Mechanical ventilation during adult surgical patients. The optimal dose tested was cardiopulmonary resuscitation with intermittent 5 mg in previous trials. This dose will be used in the positive-pressure ventilation, bilevel ventilation, or current study alone versus a combination group chest compression synchronized ventilation in a pig consisting of amisulpiride and another standard model. Crit Care Med. 42(2):89-95 antiemetic drug. In addition we will perform a study were established nausea and vomiting that occurs despite of a prophylactic dose of an antiemetic will be treated with amisulpiride. Contact Details: Funded by Accacia-Pharma Ltd. Baldingerstr. 1, 35043 Marburg, Funding period 2014 – 2016 Phone:++49 (0) 6421-58 62003 Director: Professor Dr. Hinnerk Wulf
General information about the institute Research funding 339.139,73 €
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Clinical Institutions
Department of Diagnostic and Interventional Radiology
Chair Professor A. Mahnken Summary Während Verbesserungen der Ortsauflösung meist sofort implementiert wurden, Main fields of research werden zu Beginn der Untersuchung durchgeführten Interventional Radiology Übersichtsaufnahmen mit einer unterlegenen Computed Tomography Ortsauflösung rekonstruiert. Eine Rekonstruktion der Topogramme von 50 Patienten auf die mögliche Auflösung von 0.5 mm, soll zeigen welche Research projects Verbesserung in der Darstellung und Planung Title Multicentric Non-Randomized Investigation of möglich sind. Hier ist eine Auswertung hinsichtlich RESISTANT Camouflage Stent System in Peripheral Bildqualität als auch pathologischer Befunde v.a. in Superficial Femoral Arteries der Traumadiagnostik geplant. Principal investigator(s) A. Mahnken Summary Non-randomized post-market clinical Title Evaluation alternativer Reponse Kriterien follow-up study to confirm long-term safety and Principal investigator(s) Perla Seyfer effectiveness of the CE-approved Camouflage-coated Summary Neue Responsekriterien (z.B. mRECIST, self-expandable RESISTANT Camouflage stent system Cheson, usw.) gewinnen zunehmend an Bedeutung. for revascularization of de novo stenotic lesions in Ziel ist der Transfer dieser Responsebewertungs- superficial femoral arteries in compliant patients algorithmus auf neuroendokrine Tumoren (NET). In suitable for stent angioplasty. einer Studie mit syngo.via MM Oncology soll die Funded by Eucatech AG, 79618 Rheinfelden Prognosebewertung von NETs unter Anwendung der Funding period 2013 – 2016 hepaCARE Funktionalitaet beurteilt werden. Dazu werden die Daten von 25 Patienten mit hepatisch Title Image-Based Structural and Functional metastasiertem NET vor und nach Chemo- Phenotyping of the COSYCONET Cohort Using MRI embolisation beurteilt. and CT (MR COPD) Principal investigator(s) A. Mahnken & P. Seyfer Title Establishment of in vivo C-13 magnetic Summary The medical problem addressed in this resonance spectroscopy (MRS) for tumor trial is the image-based phenotyping of COPD. The metabolism investigation principal research question is whether magnetic Principal investigator(s) A. Mahnken & A. M. König resonance imaging (MRI) can replace CT for the Summary With C-13 magnetic resonance characterization of COPD by “structural and spectroscopy (MRS) it is possible to monitor functional phenotyping” on a regional basis. The noninvasively the uptake of glucose and its sensitivity and specificity of MRI will be compared to conversion into metabolites such as lactate. This CT serving as the gold standard. opens the way to assessing metabolic activity in Funded by Heidelberg – University Medical Centre tumor tissue. This could help to characterise the Funding period 2013 – 2015 malignancy of tumors and their response of therapy. Funded by P. E. Kempkes Foundation Title Hepa Care CT Subtraction vs. Angiography - Funding period 2013 – ongoing project Vergleichende Studie zur Beurteilbarkeit der Unterschenkelgefäße mittels CT-Angiographie Title Development of a cryogenic RF coil for MRI Principal investigator(s) R. Tjiong & J. Görlach Principal investigator(s) D. Sasse & M. Völker Summary Bei Patienten mit pAVK bei denen eine Summary The research objective is to develop a konventionelle Angiographie erfolgte, erfolgt eine cryogenic RF coil for MRI with a reduced thermal CT-Angiographie incl. der Akquisition nativer CT- noise contribution. Increasing the SNR provides a Daten des Unterschenkels. Die Daten der CT- higher resolution and/or shorter measurement Angiographie mit und ohne Subtraktionstechnik times, thus extending MRI capabilities. werden mit dem Befund der intraarteriellen Funded by Foundation of the Medical Faculty, Angiographie verglichen. Zielparameter: Stenose- Philipps University Marburg detektion und Therapieentscheidung anhand der CT Funding period 2014 – 2015 Daten im Vergleich zum Goldstandard. Ziel: Überlegenheit der Subtraktions CT-Angiographie Title RF coils for dual frequency experiments in small gegenüber der Standard-CTA Technik zu zeigen. animal MRI (PhD thesis Maximilian Völker) Principal investigator(s) M. Völker & J.T. Heverhagen Title High Resolution Topogramm Summary New RF coils were developed to increase Principal investigator(s) R. Tjiong the potential of small animal MRI. The coils are
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Clinical Institutions optimized for dual frequency operation at mice. Funded by von Behring-Röntgen Foundation Phosphorus signal was used to get additional Funding period 2014 – 2016 metabolic information of tissues. Specific coils for brain, abdominal and heart MRI on mice were Title Intrafraktionale Prostata- und developed. Rektumveränderung im MRT nach Fixierung der Funded by BMBF – Federal Ministry of Education Prostata durch Positionierung eines Rektum- and Research Doppelballon versus ohne Ballon für die Funding period 2009 – 2013 Hochpräzisionsstrahlentherapie Principal investigator(s) R. Engenhart-Cabillic, G Title Semi-automatic lung segmentation method for Straßmann & M. Thiemer mri based lung images Summary Im vorliegenden Projekt soll das Ausmaß Principal investigator(s) S. Braun der intrafraktionalen Beweglichkeit der Prostata Summary The development of MR imaging of the unter Einsatz eines endorektalen Doppelballons lung is an alternative application to computer bestimmt werden. Die Messungen erfolgen in tomography in clinical routine without the Zusammenarbeit mit der Klinik für availability of computer-aided analysis for diagnose Strahlendiagnostik MRT-gestützt. Ziel ist es and treatment. We propose an alternative nachzuweisen, dass die Prostatabeweglichkeit mit postprocessing method for lung segmentation based endorektalem Doppelballon durch die Fixation on a threshold algorithm for MR images of the lung signifikant geringer ist als ohne Fixation. that was verified with several imaging sequences and different magnetic field strength. Commissioned Research Title Funktionelle Bildgebung von Title Mikrozirkulatorische und metabolische Stoffwechselvorgängen bei Zwerghamstern und Veränderungen des Skelett- und Herzmuskels bei Mäusen obstruktiver Schlafapnoe – von Genexpression und Principal investigator(s) G. Heldmaier, FB Biology & Signalling zum klinisch relevanten Readout K. Grimpo Principal investigator(s) W. Hildebrandt, R. Schulz ( Funding period 2010 – 2013 UKGM Giessen), U. Koehler, A. Kießling Summary The highly prevalent obstructive sleep Title Analyse der Tumorprogression in Maus – apnea syndrome (OSAS) is associated with Tumormordellen durch MRT Multimodale Analyse adipositas, insulin resistance and hypertension and von Gliomen im Mausmodell considered an independent cardiovascular risk Principal investigator(s) J. Bartsch, Neusurgery factor. This project focusses on in-vivo and ex-vivo analyses of skeletal muscle microcirculation and Title Oxygen damage at rat premature babies metabolism in OSAS-patients compared to age-, Principal investigator(s) K. Stieger, M. Zenlin, R. F. gender- and BMI-matched healthy controls. Maier, Children’s Hospital Marburg Investigations include muscle biopsies for histo- and Funding period 2012 – 2014 ultrastructural morphology and gene expression in combination with real-time contrast-enhanced Title MRI at epileptic mice ultrasound and Duplex-Doppler and 1H-MRS in Principal investigator(s) F. Rosenow & B. Norwood, identical localisation beside clinical blood, MRT and Department of Neurology Marburg other readouts. Funding period 2013 – 2016 Funded by von Behring-Röntgen Foundation Funding period 2011 – 2014 Title In vivo imaging of migration from dendritic cells in arthrosclerosis mouse model Title MRT-Diagnostik von gentechnisch veränderten Principal investigator(s) J. Schütt & B. Schieffer, Tumorzellen Department of Internal Medicine: Division of Principal investigator(s) J. Bartsch & M. Bauer Cardiology Marburg (Neurosurgery) Funding period 2014 – 2017 Summary Im geplanten Projekt soll die Tumorprogression verschiedener Gliomzelllinien im Title P53 – cooperation in therapy of thymus – Mausmodell umfassend untersucht werden. Hierbei lymphoma steht die Entwicklung spezifischer molekularer Principal investigator(s O. Timofeev & T. Stiewe, Sonden, sowie die Entwicklung und Optimierung der Institute of Molecular Biology and Tumorbiology MR-Sequenzen für die MR-Spektroskopie sowie die Marburg Anpassung der Analysesoftware im Vordergrund. Für Funding period 2013 – 2016 dieses Vorhaben sollen die Sonden und die Spektroskopie ex vivo an den Gliomazelllinien Title Suppression Kras – induced lung cancer by p53 untersucht und optimiert werden. Principal investigator(s) T. Stiewe, O. Timofeev,
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Clinical Institutions
Institute of Molecular Biology and Tumorbiology Burbelko M, Kalinowski M, Heverhagen JT, Marburg Piechowiak E, Kiessling, A, Figiel J, Swaid Z, Geks J, Funding period 2013 – 2016 Hundt W(2014) Prevention of type II endoleak using the AMPLATZER vascular plug before endovascular Title Shank1 and autism in mouse model aneurysm repair. Eur J Vasc Endovasc Surg 47(1):28- Principal investigator(s) S. Röskam & M. Wöhr, 36 Institute of Psychology Marburg Funding period 2010 – 2014 Contact Details: Baldingerstraße , 35043 Marburg, Tel.:++49 (0) 6421-58 66231 General information about the institute Director: Professor Dr. Andreas Mahnken
Research funding 180.185,95 €
Most important publications Isfort P, Penzkofer T, Tanaka T, Bruners P, Westphal S, Kennes LN, Schmitz-Rode T, Kuhl CK, Mahnken AH (2013) Efficacy of antegrade pyeloperfusion to protect the renal pelvis in kidney microwave ablation using an in vivo swine model. Invest Radiol 48(12):863-8
Mahnken AH, Hoffman A, Autschbach R, Damberg AL (2013) Bare metal stenting for endovascular exclusion of aortic arch thrombi. Cardiovasc Intervent Radiol 36(4):1127-31
Tanaka T, Isfort P, Braunschweig T, Westphal S, Woitok A, Penzkofer T, Bruners P, Kichikawa K, Schmitz-Rode T, Mahnken AH (2013) Superselective particle embolization enhances efficacy of radiofrequency ablation: effects of particle size and sequence of action. Cardiovasc Intervent Radiol 36(3):773-82
Steinbach S(1), Yuh EL, Burbelko M, Hundt W (2013) Detection of micrometastases of squamous cell carcinoma tumor cells in muscle tissue. Anticancer Res 33(12):5213-21
Apitzsch JC, Westphal S, Penzkofer T, Kuhl CK, Knüchel R, Mahnken AH (2014) The use of contrast- enhanced post Mortem CT in the detection of cardiovascular deaths. PLoS One 23;9(4):e93101
Penzkofer T, Slebocki K, Grommes J, Bruners P, Isfort P, Schmitz-Rode T, Langer S, Kuhl CK, Mahnken AH (2014) High-pitch carbon dioxide contrasted CT angiography: pilot study. Cardiovasc Intervent Radiol 37(2):362-70
Seyfer P, Pagenstecher A, Mandic R, Klose KJ, Heverhagen JT (2014) Cancer and inflammation: differentiation by USPIO-enhanced MR imaging. J Magn Reson Imaging 39(3):665-72
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Department of Nuclear Medicine
Chair Professor M. Luster Riera-Knorrenschild, Department of Hematology, Oncology and Immunology Main fields of research Summary This study is a randomized, multi-center During the reporting period the capacity of the study that will compare the efficacy and safety of radiochemical laboratory was expanded by the selective internal radiation therapy (SIRT) using SIR- installation of a Germanium/Gallium-68 radionuclide Spheres microspheres plus a standard chemotherapy generator and a computer-controlled device for the regimen of FOLFOX6m versus FOLFOX6m alone as automated synthesis of radiopharmaceuticals, in first-line therapy in patients with non-resectable particular radiopeptides in the rapidly expanding liver metastases from primary colorectal carcinoma. field of “theranostics”. Thus the diagnostic spec,trum Funded by Sirtex Technologgy, Sydney; Australia could be complemented by Ga-68-DOTATOC-PET/CT Funding period 2013 – 2015 for staging of neuroendocrine tumors and Ga-68- Title A Multicenter, Randomized, Double-Blind, PSMA-PET/CT for imaging of prostate cancer. Placebo-Controlled, Phase III Study of ARN-509 in Furthermore the corresponding radiopharma- Men with Non-Metastatic (M0) Castration-Resistant ceuticals can be used for radionuclide therapy of Prostate Cancer metastases or in some cases primary lesions of the Principal investigator(s) J. Heinis, J. Olbert, same entities by labeling the compounds with Lu- Department of Urology and Paediatric Urology, 177 or Y-90. This approach also offers the possibility University of Marburg & A. Heidenreich, Department of an individual pretherapeutic dosimetry in order to of Urology, University of Aachen optimize the absorbed radiation dose to the tumor Summary The purpose of this study is to evaluate while minimizing the radiation exposure of the the efficacy and safety of ARN-509 in adult men with patient i.e. the organs at risk. For this purpose high-risk non-metastatic castration-resistant appropriate novel software tools were introduced prostate cancer. and their feasibility was investigated. Individual Funded by Pharmaceutical Research Associates dosimetry could be already successfully established GmbH, Mannheim during the reporting period in the field of Funding period 2013 – 2015 radioiodine therapy of thyroid cancer and in the management of neuroendocrine malignancies. A Title A Randomized, Double-blind, Phase 3 Efficacy new field of research is the use of targeted therapies Trial of PROSTVAC-V/F ± GM-CSF in Men With i.e. tyrosinekinase- inhibitors for the treatment of Asymptomatic or Minimally Symptomatic advanced thyroid tumors namely radioiodine Metastatic, Castrate-Resistant Prostate Cancer refractory thyroid cancer. Principal investigator(s) J. Heinis & P. J. Olbert, Department of Urology and Paediatric Urology, Research projects Marburg Title A Randomised, Double Blind Study of Compare Summary The purpose of this study is to determine the Complete Remission Rate Following a 5-Week whether PROSTVAC alone or in combination with Course of Selumetinib or Placebo and Single Dose GM-CSF is effective in prolonging overall survival in Adjuvant Radioactive Iodine Therapy in Patients with men with few or no symptoms from metastatic, Differentiated Thyroid Cancer (under review) castrate-resistant prostate cancer. Principal investigator(s) M. Kreißl & M. Luster Funded by Nordic, Inc.; PPD Immuno Therapeutics Summary The study is designed to evaluate the Funding period 2011 – 2015 clinical efficacy, safety and tolerability of selumetinib with radioactive iodine therapy in patients with Title PRESENT: Prevention of Recurrence in Early differentiated thyroid cancer. Stage, Node-Positive Breast Cancer with Low to Funded by AstraZeneca AB, Södertälje, Schweden Intermediate HER2 Expression with NeuVax TM Funding period 2013 – 2015 Treatment (Phase 3) Principal investigator(s) D. Librizzi, & Dr. K. Title FOXFIREGlobal: Assessment of Overall Survival Baumann, Department of Gynecology, Gynecological of FOLFOX6m plus SIR-Spheres microspheres versus Endocrinology and Oncology, Marburg FOLFOX6m alone as first-line treatment in patients Summary Purpose of this trial: To assess the efficacy with non-resectable liver metastases from primary and safety of NeuVax™ administered with adjuvant colorectal carcinoma in randomised clinical study Leukine® (sargramostim, GM-CSF).To evaluate and Principal investigator(s) A. Pfestroff, H. Höffken & J. compare the disease free survival (DFS) in the vaccinated and control subjects
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Clinical Institutions
Funded by Galena Biopharma, Inc. not previously received chemotherapy for their liver Funding period 2011 – 2015 metastases). Funded by Sirtex Medical Title QUEST Study: Quantitative Uptake Evaluation in Funding period 2006 – 2018 SIR-Spheres Therapy Principal investigator(s) A. Pfestroff Title Pilotprojekt zur Quantifizierung und Summary The QUEST (Quantitative Uptake Eindringtiefe von Radiopharmaka durch nächtliche Evaluation in SIR-Spheres Therapy) study is an nasale Langzeitinhalation (NLI) bei Patienten mit investigator based initiative to understand the dose- COPD response relationship in Y-90 radioembolisation Principal investigator(s) D. Librizzi, Dr. Pfestroff, treatment of liver cancer. Based on results from the Prof. Groß (FH Gießen) & U. Koehler; Division of site assessment phase to characterize scanners, a Pneumology Marburg clinical protocol is proposed for image acquisition Summary Ventilationsszintigraphie mit nasalem and analysis in an attempt to standardize the Applikationsweg vs. oralem Applikationsweg. Zur approach to dosimetry in this study. Etablierung einer neuen Therapieform bei COPD. Funded by Sirtex Technology Pty Ltd, Sydney, Funded by LOEWE Australia Funding period 2011 – 2014 Funding period 2013 – 2014 Title The Parkinson’s Progression Markers Initiative Title ReBeL study: A randomized phase I/II trial of (PPMI) lenalidomide and rituximab with or without Principal investigator(s) H. Höffken & Prof. B. bendamustine in patients ≥ 18 years with relapsed Mollenhauer, Paracelsus-Elena Clinic Kassel follicular lymphoma Summary The mission of PPMI is to identify one or Principal investigator(s) H. Höffken & C. Wilhelm, more biomarkers of Parkinson’s disease progression. Department of Hematology, Oncology and The discovery of a biomarker is a critical step in the Immunology, Marburg development of new and better treatments for PD. Summary For the phase I part of the study: to Funded by The Michael J. Fox Foundation for determine the dose limiting toxicity (DLT) and Parkinson’s Research (MJFF) recommended dose level (RDL)of lenalidomide and Funding period 2010 – 2018 bendamustine given in combination withrituximab for the phase II part of the studyFor the phase II of the study: to determine the efficacy and toxicity of the two arms of the study (arm A: lenalidomide and General information about the institute rituximab, and arm B: lenalidomide, rituximab andbendamustine) in patients with relapsed Research funding 12.564,62 € follicular lymphoma Funded by HOVON ClinAssess GmbH (Monitoring), Leverkusen Most important publications Funding period 2012 – 2015 Hänscheid H, Canzi C, Eschner W, Flux G, Luster M,
Strigari L, Lassmann M (2013) EANM Dosimetry Title SIRFLOX-Study: Randomised Comparative Study Committee series on standard operational Of Folfox6m Plus Sir-Spheres® Microspheres Versus procedures for pre-therapeutic dosimetry II. Folfox6m Alone As First Line Treatment In Patients Dosimetry prior to radioiodine therapy of benign With Nonresectable Liver Metastases From Primary thyroid diseases. Eur J Nucl Med Mol Imaging Colorectal Carcinoma Primary 40(7):1126-34 Principal investigator(s) A. Pfestroff, H. Höffken & J.
Riera-Knorrenschild, Department of Hematology, Weber T, Maier-Funk C, Ohlhauser D, Hillenbrand A, Oncology and Immunology, Marburg Cammerer G, Barth TF, Henne-Bruns D, Boehm BO, Summary The SIRFLOX study is an international Reske SN, Luster M (2013) Accurate preoperative research study designed to evaluate a new localization of parathyroid adenomas with C-11 treatment option for patients with colorectal cancer methionine PET/CT. Ann Surg 257(6):1124-8 that has undergone metastatic spread to the liver.
The study is designed to evaluate whether FOLFOX Pitoia F, Bueno MF, Abelleira E, Salvai ME, Bergoglio chemotherapy in combination with Selective Internal L, Luster M, Niepomniszcze H (2013) Undetectable Radiation Therapy is more effective than pre-ablation thyroglobulin levels in patients with chemotherapy alone. This study represents the first differentiated thyroid cancer: it is not always what it time that these treatments have been assessed seems. Arq Bras Endocrinol Metabol 57(4):300-6 together as part of a randomized controlled study and as a first-line therapy (i.e. in patients who have
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Clinical Institutions
Luster M, Musholt TJ (2013) Thyroid gland: thyroid surgery and radioiodine ablation-the surgeon's role. Nat Rev Endocrinol 9(3):140-1
Thies ED, Tanase K, Maeder U, Luster M, Buck AK, Hänscheid H, Reiners C, Verburg FA (2014) The number of 131I therapy courses needed to achieve complete remission is an indicator of prognosis in patients with differentiated thyroid carcinoma. Eur J Nucl Med Mol Imaging 41(12):2281-90
Schlumberger M, Brose M, Elisei R, Leboulleux S, Luster M, Pitoia F, Pacini F (2014) Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol 2(5):356-8
Rossmann A, Mandic R, Heinis J, Höffken H, Küssner O, Kinscherf R, Weihe E, Bette M (2014) Intraperitoneal oxidative stress in rabbits with papillomavirus-associated head and neck cancer induces tumoricidal immune response that is adoptively transferable. Clin Cancer Res 20(16):4289- 301
Luster M, Weber T, Verburg FA (2014) Differentiated thyroid cancer-personalized therapies to prevent overtreatment. Nat Rev Endocrinol 10(9):563-74
Contact Details: Baldingerstrasse , 35043 Marburg, Phone:++49 (0) 6421-58 62815 Director: Professor Dr. Markus Luster
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Department of Radiotherapy and Radiooncology
Chair Professor R. Engenhart-Cabillic Summary Evidence is needed to assess if particle therapy outperforms conventional radiotherapy. Main fields of research ROCOCO aims at demonstrating through in silico Clinical focus trials that particle therapy: (1) decreases irradiation of normal tissue and therefore risk of side effects Clinical application and technical development of and secondary tumors, (2) increases iso-toxic tumor stereotactic radiotherapy and other high control probability, hence local control and survival precision techniques rates in head and neck, prostate and lung cancer. Adaptive radiotherapy planning for photon and
particle therapy Title Development of ultra-fast dose computation
algorithms for radiotherapy Physical and Technical focus Principal investigator(s) U. Jelen & F. Ammazzalorso Monte Carlo methods for treatment planning and Summary The conformity of advanced radiotherapy quality assurance modalities requires extensive dosimetric verification, Dosimetry and quality assurance in sophisticated potentially combined with on-line treatment plan radiotherapy techniques with emphasis on adaptation. The prohibitive dose computation times particle radiotherapy and irradiation of small have hinder the application of such techniques in the targets clinical routine. This project proposes an ultra-fast
multi-modality (photon/proton/carbon-ion) Biological focus analytical dose computation engine exploiting Biological radiotherapy planning by means of general purpose graphic processing units (GPGPU). biophysical modeling Funded by Parts of the project were funded: Methods to overcome resistance with focus on DFG – German Research Foundation: Support of the hypoxia Initiation of International Collaboration Treatment response in human papilloma virus Alfred und Ursula Kulemann Foundation support for induced head and neck squamous cell cancer hardware purchase
Research projects Title Biological radiotherapy planning by means of Title Union of Light-Ion Centers in Europe (ULICE) biophysical modeling of the tumor control Principal investigator(s) R. Orecchia, Centro probability in particle beam therapy Nazionale di Adroterapia Oncologica, Milan (project Principal investigator(s) A. Wittig, U. Jelen, A. coordinator), Marburg: U. Jelen, F. Ammazzalorso & Santiago & M.-A. Chanrion A. Wittig For radiotherapy treatment planning, the increased Summary ULICE comprises more than 20 academic biological effectiveness of carbon ions must be and industrial partners, aiming at development of quantified through a biophysical model. One such instruments and protocols for particle therapy and model, is the local effect model (LEM). Purpose of increase inter-facility clinical cooperation. Marburg this work is to validate the computational results participates in WP5 (Adaptive Treatment Planning), obtained with the LEM model against the available WP10 (European Standardization of Clinical clinical data and to provide the best estimate of the Protocols) and WP11 (Transnational Access). In WP5 α/β, to be used as input for LEM, for tissues where Marburg is involved with patient immobilization, the verification against the clinical follow-up data is dosimetric stability and tool development for not possible. particle therapy treatment planning and delivery. Funded by Anneliese Pohl Foundation Funded by European Commission (FP7) Funding period 2012 – 2014 Funding period 2009 – 2014 Title Evaluation of the clinical outcome of high Title Radiation Oncology Collaborative Comparison precision and stereotactic techniques in terms of (ROCOCO). In Silico clinical trial in lung, prostate and tumor control and side effects head cancer, comparing photons, protons and C-ion Principal investigator(s) A. Wittig, R. Engenhart- therapy treatment: a multicentric planning study Cabillic, Prof. Fritz (Siegen) based on a reference dataset of patients. Summary Highly precision radiotherapy techniques Principal investigator(s) P. Lambin, Maastricht aim at conforming the dose to the target thus Radiation Oncology, Maastricht, Marburg: U. Jelen & enabling escalation of the biologically effective dose F. Ammazzalorso & A. Santiago in the tumor and/or sparing of normal tissues. The project aims at evaluation of clinical follow up data
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Clinical Institutions with focus on mature long term data in patients Funded by UKGM, University Medical Centre Giessen treated with precision techniques for lung or brain / Marburg lesions. Funding period 2012 – 2014
Title Study on the technical implementation of Title Role of hypoxia-inducible transcription factors particle therapy for treatment of pulmonary lesions for the treatment efficacy of carbon ion radiation Principal investigator(s) A. Wittig, U. Jelen, A. compared to photons in the lung cancer model Santiago, R. Engenhart-Cabillic & Prof. Fritz (Siegen) Principal investigator(s) F. Rose, J. Hänze & F. Subtil Summary The challenge of particle therapy in the Summary Radiation resistance of solid tumors lung is the management of respiratory motion, due towards photon irradiation is caused by attenuated to the sensitivity of the ion range to changes in the amounts of DNA-damage in less oxygenated tumor water equivalent path length. The feasibility of High areas and by increased Hypoxia-inducible factor 1 Frequency Jet Ventilation (HFJV) as compared to (HIF-1) signaling. We analyzed the effect of HIF-1 alternative techniques for breathing control is signaling after irradiation with photons in evaluated based on data of patients treated with comparison to carbon ions using biological stereotactic photon radiotherapy and the respective equivalent doses in a human non-small cell lung techniques for motion control. cancer model. Knockdown of HIF-1α in vivo combined with photon irradiation delayed tumor Title Optimization of the dosimetric quality and growth. Photon irradiation induced HIF-1α and stability of heavy ion therapy planning target genes predominantly in oxygenated cells with Principal investigator(s) U. Jelen & F. Ammazzalorso subsequently enhanced tumor angiogenesis in Summary Conformity offered by particle therapy contrast to carbon ion irradiation. Micro-DNA array requires tighter tolerances for dosimetric analysis indicated that photons but not carbon ions uncertainties, e.g. patient setup, CT calibration. induced components of the mTOR (mammalian Tools for dosimetrically robust treatment plans, like target of rapamycin) pathway as relevant for HIF-1α the Port Homogeneity Index were developed in induction. Importantly after carbon ion irradiation in Marburg. In this project (1) a comprehensive study vivo, we observed substantially decreased HIF-1α of the robustness problem, (2) substantial levels and drastically delayed tumor growth improvements to the PHI concept and (3) its indicating a higher relative biological effectiveness complete software implementation, for clinical than anticipated from the cell survival data. In application, are proposed. conclusion, carbon ions mediate an improved therapeutic effectiveness without tumor promoting Title KoHaLa HIF-1 signaling. Principal investigator(s) H. Vorwerk, G. Sakas Funded by DFG – German Research Foundation MedCom GmbH), F. Wesang (Frauenhofer IGD), D. Funding period 2009 – 2013 Baltas (Clinical Centre Offenbach) Summary Development and testing of an automated Title Role of bacterial pathogenicity in promoting contouring atlas for patients with head and neck mechanisms of radioresistence in NSCLC cancer. Principal investigator(s) F. Subtil , K. Hattar (Gießen) Funded by LOEWE & U. Grandel (Gießen) Funding period 2012 – 2014 Summary Lung cancer is frequently complicated by pulmonary infections which may impair prognosis of Title Adaptive radiotherapy: daily patient related this disease. We hypothesize that purified dose reconstruction in fluence modulated endotoxin, the main pathogenicity factor of gram- radiotherapy techniques negative bacteria, promotes radioresistance. Principal investigator(s) H. Vorwerk, D. Wolff & D. Therefore, we investigated the effect of bacterial Wolf (Gießen) lipopolysaccharides (LPS) on tumor proliferation in Summary The project aims at the evaluation of 3D- combination with photon irradiation in different imaging for patient positioning at linear accelerators non-small cell lung cancer (NSCLC) cell lines. Further, and includes the development of methods for we plan to investigate the molecular mechanism, calibration of conebeam-CTs for calculation of the which may be involved in this LPS-induced photon dose distribution and methods for online radioresistance. measurements of the fluence in intensity modulated Funded by von Behring-Röntgen Foundation techniques. Such is used for calculation of the daily Funding period 2013 – 2015 dose distribution in fractionated treatments. The clinical evaluation of reconstructed dose Title Development of individualized treatment distributions helps in developing protocols for safety concepts in head and neck malignancies by margins in image guided radiotherapy. combined modalities
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Clinical Institutions
Principal investigator(s) Prof. R. Dr. Engenhart- follow up in 164 patients of a single institution. J Cabillic, Priv.-Doz. Dr. A. Wittig, Dr. A. Arenz, Dr. S. Neurol 260(8): 2156-2162 Wagner, Prof. Dr. C. Wittekind, Prof. Dr. J.P. Klußmann Ammazzalorso F, Graef S, Weber U, Wittig A, Summary HPV related cancers of the oropharynx Engenhart-Cabillic R, Jelen U: Dosimetric represent a different clinicopathological and consequences of intrafraction prostate motion in molecular entity compared to not HPV-related scanned ion beam radiotherapy. Radiother Oncol tumors. Regardless of a superior treatment response 2014 May 12. pii: S0167-8140(14)00165-0 [Epub in HPV-related tumors, both groups are treated with ahead of print] the same treatment regimes. Aim of the research projects is to elucidate the molecular mechanisms Fokas E, Henzel M, Surber G, Hamm K, Engenhart- leading to a higher efficacy of ionizing irradiation in Cabillic R. (2014) Stereotactic radiotherapy of benign HPV-related cancer and to understand and meningeoma in the elderly: clinical outcome and overcome radioresistance in HPV negative tumors, toxicity in 121 patients. Radiother Oncol 111(3):457- mainly by using combined modalities. 62. Funded by UKGM – University Medical Centre Giessen / Marburg Fokas E, Henzel M, Surber G, Hamm K, Engenhart- Funding period 2012 – 2014 Cabillic R. (2014) Stereotactic radiation therapy for benign meningeoma: long-term outcome in 318 Title Optimization of the irradiation effect through patients. Int J Radiat Oncol Biol Phys 89(3):569-75 modulation of autophagy in radioresistent tumor cell lines Subtil FS, Wilhelm J, Bill V, Westholt N, Rudolph S, Principal investigator(s) C. Akrpowitz & A. Arenz Fischer J, Scheel S, Seay U, Fournier C, Taucher- Summary Autophagy serves as a pro-death Scholz G, Scholz M, Seeger W, Engenhart-Cabillic R, mechanism but also as a protective cell survival Rose F, Dahm-Daphi J, Hänze J (2014) Carbon ion mechanism causing resistance to anticancer radiotherapy of human lung cancer attenuates HIF-1 therapies. We investigate the effects of radiation- signaling and acts with considerably enhanced and hypoxia-induced autophagy on survival of therapeutic efficacy. FASEB J28(3):1412-21 cancer cells of different entities. Targeting the pro- death and pro-survival functions of autophagy we evaluate cellular survival after inhibition or induction of autophagy. Depending on the cellular features, Contact Details: either induction or inhibition of autophagy can Baldingerstr. 1, 35043 Marburg, provide therapeutic benefits in vitro offering Tel.:++49 (0) 6421-58 66434 opportunities to personalized medicine strategies. Director: Professor Dr. Rita Engenhart-Cabillic Funded by P.E. Kempkes Foundation Funding period 2012 – 2014
General information about the institute
Research funding 499.385,37 €
Most important publications Santiago A, Jelen U, Ammazzalorso F, Engenhart- Cabillic R, Fritz P, Mühlnickel W, Enghardt W, Baumann M, Wittig A (2013) Reproducibility of target coverage in stereotactic spot scanning proton lung irradiation under high frequency jet ventilation. Radiother Oncol 2013 Oct 12. doi:pii: S0167- 8140(13)00475-1. 10
Fokas E, Henzel M, Wittig A, Grund S, Engenhart- Cabillic R (2013) Stereotactic radiosurgery of cerebral arteriovenous malformations: long-term
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Clinical Institutions
Department of Internal Medicine: Division of Gastroenterology, Endocrinology and Metabolism
Chair Professor T. Gress Summary Mechanisms of the oncogenetic Professor V. Ellenrieder senescence overcoming in the transgenic mouse model of the pancreatic carcinogenesis Main fields of research Funded by UKGM – University Medical Centre Giessen / Marburg Clinical and molecular gastrointestinal oncology, Funding period 2012 – 2013 early detection of GI tumors, preneoplastic lesions of
GI-tumours, endoscopy, chronic inflammatory bowel Title Genome-wide analysis of the CUX1 disease, acute and chronic pancreatitis, transcriptional network mediating resistance to neuroendocrine tumours, functional genome apoptosis in pancreatic cancer: Continuation of analysis of GI tumors, molecular diagnosis and Clinical Research Group therapy, molecular mechanisms of cancerogenesis in Principal investigator(s) P. Michl GI-tract, hereditary disease of GI-tract, NFAT and Funded by DFG – German Research Foundation TGF-signal transduction, transcriptional regulation Funding period 2012 – 2015 of gene expression, fibrogenesis in the pancreas.
Title EPC-TM-Net Targeting the tumor Research projects microenvironment to improve pancreatic cancer Title Role of transcription factors NFATc1 in the prognosis leukaemia genesis and therapy resistance of FLT3- Principal investigator(s) T. Gress ITD-positive AML Funded by EU – European Research Council Principal investigator(s) A. Burchert & V. Ellenrieder Funding period 2011 – 2014 Funded by José Carreras Leukaemia Foundation Funding period 2012 – 2015 Title Analysis of microRNA profiles depending on K- ras and B-raf mutations in colon cancer: a combined Title NGFN-plus "Translational Genome Network for assessment on the PETACC-2-trial pancreas carcinoma" Principal investigator(s) P. Michl Principal investigator(s) T. Gress, project Funded by EORTC – European organization for coordinator Research and Treatment of Cancer Funded by BMBF – Federal Ministry of Education Funding period 2012 – 2014 and Research Funding period 2008 – 2013 Title Characterization and therapeutic targeting of cathepsin activity in tumor-associated macrophages Title KMU-innovativ-4: PakaNostra during pancreatic cancer development and Principal investigator(s) M. Buchholz progression Summary TP6 Identification and validation of drug Principal investigator(s) P. Michl targets of pancreas carcinomas by innovative Funded by DFG – German Research Foundation strategies Funding period 2014 – 2017 Funded by BMBF – Federal Ministry of Education and Research Title Interactions between SSTR modulation via Funding period 2010 – 2013 lanreotide and TKIs in sequential and combination approaches in vitro and in vivo Title Identification of new therapeutic targets using Principal investigator(s) S. Krug & P. Michl RNA interference library screens to resolve chemo Summary resistance at pancreas carcinoma Funded by IPSEN Pharma GmbH Principal investigator(s) P. Michl Funding period 2014 – 2016 Funded by Deutsche Krebshilfe Funding period 2010 – 2013 Title Resistenzmechanismen auf antiangiogene Therapieansätze bei Neuroendokrinen Neoplasien - Title Mechanisms of the oncogenetic senescence Charakterisierung molekularer Mechanismen u. overcoming in the transgenic mouse model of the Identifizierung prädiktiver Marker pancreatic carcinogenesis Principal investigator(s) S. Krug & P. Michl Principal investigator(s) S. Baumgart & V. Ellenrieder Funded by UKGM Funding period 2014 – 2016
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Clinical Institutions
Title Pharmakologische Immunmodulation im investigate safety and efficacy of gemcitabine transgenen RIP-Tag-Modell combined with cetuximab as adjuvant therapy in Principal investigator(s) S. Krug & P. Michl pancreatic cancer (ATIP). Ann Oncol : 24, 2576-81 Funded by Theranostics Research Netwrok Funding period 2013 – 2014 Artal-Martinez de Narvajas A, Gomez TS, Zhang JS, Mann AO, Taoda Y, Gorman JA, Herreros-Villanueva Title Charakterisierung der molekularen M, Gress TM, Ellenrieder V, Bujanda L, Kim DH, Mechanismen der CUX1-induzierten Angiogenese Kozikowski AP, Koenig A, Billadeau DD. (2013) bei Neuroendokrinen Neoplasien Epigenetic regulation of autophagy by the Principal investigator(s) S. Krug & P. Michl methyltransferase G9a. Mol Cell Biol. 33, 3983-93 Summary WNT5A - mediator of resistance to apoptosis in pancreatic cancer Neesse A, Hahnenkamp A, Griesmann H, Buchholz Funded by Röntgen-Behring Foundation M, Hahn SA, Maghnouj A, Fendrich V, Ring J, Sipos B, Funding period 2014 – 2016 Tuveson DA, Bremer C, Gress TM, Michl P (2013) Claudin-4-targeted optical imaging detects Title Connective tissue groth factor (CTGF) im pancreatic cancer and its precursor lesions. Gut duktalen Pankreaskarzinom: Funktionelle und 62:1034-1043 therapeutische Evaluation in Maus und Mensch Principal investigator(s) A. Neese Potjer TP, Schot I, Langer P, Heverhagen JT, Wasser Funded by UKGM – University Medical Centre MN, Slater EP, Klöppel G, Morreau HM, Bonsing BA, Giessen / Marburg de Vos Tot Nederveen Cappel WH, Bargello M, Gress Funding period 2013 – 2014 TM, Vasen HF, Bartsch DK; Leiden Familial Pancreatic Cancer Group; FaPaCa registry. (2013) Variation in Title Analyse der extrinsischen (Anti-) precursor lesions of pancreatic cancer among high- Apoptosemechanismen des HCC in Abhängigkeit des risk groups. Clin Cancer Res.19, 442-449 Survival Faktors CUX1 - Zusammenhang des TRAIL Pathways und CUX1 Baumgart S, Chen NM, Siveke JT, Konig A, Zhang JS, Principal investigator(s) L. Doll & T. Wissniowski Singh SK, Wolf E, Bartkuhn M, Esposito I, Hessmann Funded by P.E. Kempkes Foundation E, Reinecke J, Nikorowitsch J, Brunner M, Singh G, Funding period 2014 – 2015 Fernandez-Zapico ME, Smyrk T, Bamlet WR, Eilers M, Neesse A, Gress TM, Billadeau DD, Tuveson D, Title CAM-PaC (Integrative Analysis of Gene Urrutia R, Ellenrieder V (2014) Inflammation- Functions in Cellular and Animal Models of induced NFATc1-STAT3 transcription complex Pancreatic Cancer promotes pancreatic cancer initiation by KrasG12D. Principal investigator(s) M. Buchholz & T. M. Gress Cancer Discov 4: 688-701 Funded by EU – European Research Council Funding period 2013 – 2018 Kaistha BP, Honstein T, Muller V, Bielak S, Sauer M, Kreider R, Fassan M, Scarpa A, Schmees C, Volkmer H, Gress TM, Buchholz M (2014). Key role of dual Most important publications specificity kinase TTK in proliferation and survival of Michl P, Gress TM (2013)Current concepts and novel pancreatic cancer cells. Br J Cancer 111: 1780-1787 targets in advanced pancreatic cancer. Gut 62: 317- 26 Krug S, Kuhnemuth B, Griesmann H, Neesse A, Muhlberg L, Boch M, Kortenhaus J, Fendrich V, Hart PA, Kamisawa T, Brugge WR, Chung JB, Culver Wiese D, Sipos B, Friemel J, Gress TM, Michl P (2014) EL, Czakó L, Frulloni L, Go VL, Gress TM, Kim MH, CUX1: a modulator of tumour aggressiveness in Kawa S, Lee KT, Lerch MM, Liao WC, Löhr M, Okazaki pancreatic neuroendocrine neoplasms. Endocr Relat K, Ryu JK, Schleinitz N, Shimizu K, Shimosegawa T, Cancer 21: 879-890. Soetikno R, Webster G, Yadav D, Zen Y, Chari ST. (2013) Long-term outcomes of autoimmune Hermann PC, Sancho P, Cañamero M, Martinelli P, pancreatitis: a multicentre, international analysis. Madriles F, Michl P, Gress T, de Pascual R, Gandia L, Gut 62: 1771-1776 Guerra C, Barbacid M, Wagner M, Vieira CR, Aicher A, Real FX, Sainz B Jr, Heeschen C. (2014) Nicotine Fensterer H, Schade-Brittinger C, Müller HH, Tebbe promotes initiation and progression of KRAS-induced S, Fass J, Lindig U, Settmacher U, Schmidt WE, pancreatic cancer via Gata6-dependent Märten A, Ebert MP, Kornmann M, Hofheinz R, dedifferentiation of acinar cells in mice. Endlicher E, Brendel C, Barth PJ, Bartsch DK, Michl P, Gastroenterology 147, 1119-33 Gress TM; Arbeitsgemeinschaft Internistische Onkologie. (2013) Multicenter phase II trial to
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Clinical Institutions
Professor P. Kann – Funding period 2003 – 2015 Endocrinology & Diabetology Title Development of a multimodal score to monitor Main fields of research the effects of growth hormone substitution in Pituitary Diseases: Growth Hormone hypopituitarism Substitution, Pharmacogenetics, Somatotrophic Principal investigator(s) P. H. Kann Function and Cancer Risk Summary Observational, prospective clinical study - Diabetes Mellitus: Epidemiology, Treatment, Growth hormone deficiency and efficacy of Hemochromatosis treatment (GET), Study: to develop and establish a score that integrates the multimodal effects of Osteology: Osteoporosis - Diagnosis and growth hormone substitution. Treatment, Mechanical Properties of Bone Funded by Novo Nordisk Pharma GmbH Tissue, Migrants’ Osteomalacia Funding period 2009 – 2015 Neuroendocrine Tumors: Endocrine Imaging -
Endoscopic Ultrasound, Multiple Endocrine Title Seascape Study Neoplasia, Insulinoma Principal investigator(s) G. K. Stalla, Munich Diseases of the Adrenal Glands: Adrenal Summary An open-label, multi-center, expanded Incidentaloma, Primary Hyperaldosteronism, access study of pasireotide s.c. in patients with Pheochromocytoma Cushing’s disease (IIIb) Medical Anthropology: Cultural / Social Change Funded by Novartis Pharma GmbH and the Risk for Metabolic Diseases in Funding period 2011 – 2013 Subsaharian Africa
Laboratory Medicine Title KIMS Pharmacogenetics Study – Pharmacogenetics of growth hormone substitution Research projects Principal investigator(s) P. H. Kann Title Association of the GHRd3-polymorphism to risk Summary Aim of this study is to correlate genetic and prognosis of breast cancer features with clinical data and responsiveness to the Principal investigator(s) P. H. Kann individually required recombinant human growth Summary Analysis of the association between the hormone dose of adult patients with pituitary growth hormone receptor deletion exon 3 (GHRd3)- growth hormone deficiency caused by trauma, polymorphism with the development of breast tumor, surgery, inflammation or idiopathic origin cancer – a cross-sectional diagnostic study, collected in the international long-term follow-up molecular genetics study KIMS (Pfizer International Metabolic Funded by DFG – German Science Foundation Database). Funding period 2010 – 2013 Funded by Pfizer Pharma GmbH Funding period 1999 – 2013 Title Change in culture and lifestyle and the risk for diabetes mellitus, metabolic syndrome and Title GHRd3 gene polymorphism and IGF1 serum osteoporosis concentration at baseline in the German KIMS Principal investigator(s) P. H. Kann & P. Nyarango, cohort University of Namibia, Windhoek, Namibia Principal investigator(s) P. H. Kann Summary Do cultural change and the alteration of Summary Non-interventional diagnostic study to the style of living modulate the risk for diabetes investigate whether the GHRd3 polymorphism which mellitus type 2 and osteoporosis in subsaharian has been shown to be related to the responsiveness africa? A diagnostic study in cooperation with the to GH treatment previously might be related to basal Ovahimba people in Kunene / north-western IGF1 serum concentrations in the KIMS cohort and Namibia explain the prevalence of subjects with IGF1 serum Funded by Novo Nordisk Pharma GmbH, concentrations within the age- and sex-related International Diabetes Federation normal range at baseline in a cohort of patients with Funding period 2011-2013 growth hormone deficiency / hypopituitarism. Funded by Pfizer Pharma GmbH Title Growth hormone substitution in childhood and Funding period 2012 – 2015 adulthood (NordiWin/GrowthWin) Principal investigator(s) S. Meckes-Ferber, Mainz Title Pituitary function in patients with hereditary Summary Observational Study - Effects and safety of hemochromatosis growth hormone replacement in subjects with Principal investigator(s) P. H. Kann growth hormone deficiency due to an organic Summary Cross-sectional diagnostic study to disease of the pituitary gland determine the prevalence of deficiences of pituitary Funded by Novo Nordisk Pharma GmbH
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Clinical Institutions functions in patients with genetically determined Title Zoledronic acid versus alendronate in hemochromatosis postmenopausal osteoporosis Funded by Novo Nordisk Pharma Principal investigator(s) P. Hadji, Professor of Funding period 2008 – 2014 Gynecology, Marburg Summary Prospective clinical study to determine Title Endoscopic ultrasound of pancreatic fracture risk, quality of life and health status under neuroendocrine tumors – evaluation of diagnostic treatment with zoledronic acid and generic criteria alendronate in postmenopausal women with low Principal investigator(s) P. H. Kann, bone mass Summary prospective diagnostic study to establish Funded by Novartis Pharma GmbH diagnostic and prognostic criteria for pancreatic Funding period 2007-2013 neuroendocrine tumors occurring sporadically and in genetic diseases, especially MEN1. Title Pituitary adenylate cyclase activating Funded by funded by Novartis Pharma GmbH 1995- polypeptide in stressed patients with multiple 2005, at this time not funded sclerosis (MS) or clinically isolated syndrome Project period 1995-2014 suggestive for MS under treatment with glatiramer acetate (PACAMUS) Title In vitro assessment of mechanical properties of Principal investigator(s) B. Tackenberg, Marburg bone tissue Summary Prospective clinical study to collect data Principal investigator(s) S. Ruchholtz, Professor of on biological and psychological stress parameters Surgery, Marburg and their influence on neuroendocrine circuits in Summary In vitro study to determine whether patients with multiple sclerosis embalmed and/or fresh frozen human bones in Funded by Sanofi Aventis orthopaedic cadaveric studies are authentic and Funding period 2009 – 2015 feasible to describe mechanical properties of bone tissue. Title Cultural Neuroscience – neuronal processes, social interactions and conflicts Title Evaluation of ultrasound transmission velocity Principal investigator(s) T. Kircher, Professor of and 3-dimensional radiology in different bone types Psychiatry, Marburg; U. Wagner, Professor of for dental implantology: a comparative ex vivo study Psychology, Marburg Principal investigator(s) B. Al-Nawas, Professor of Summary Experimental study to investigate Orofacial Surgery, Mainz neuronal correlates of processes of social Summary Characterization of mechanical properties categorization including endocrine parameters of bone tissue by ultrasound to determine an Funded by LOEWE appropriate diagnostic procedure to plan surgical Funding period 2010 – 2015 strategies in orofacial surgery. Funded by Johannes Gutenberg University Mainz Title Study on migrants’ osteomalacia Funding period 2006 – 2013 Principal investigator(s) U. Lange, Professor of Rheumatology, Bad Nauheim Title Partial pancreaticoduodenectomy in duodenal Summary Experimental study on molecular genetics gastrinoma associated with multiple endocrine of migrants’ osteomalacia – characterization of neoplasia type 1 polymorphisms of specific candidate genes for Principal investigator(s) D. K. Bartsch, Professor of osteoporosis/osteomalacia, a comparison between Surgery, Marburg Germans and Turkish immigrants living in Germany Summary Long-term monitoring and therapeutical Funded by Justus Liebig University Gießen decision-making processes in patients with MEN1 Funding period 2011 – 2016
Title Relation between bone quality values from Title Tumors of the adrenal glands – hormonally ultrasound transmission velocity and implant inactive and subclinical Cushing’s syndrome not stability parameters – an ex vivo study requiring surgical treatment: a longitudinal follow-up Principal investigator(s) B. Al-Nawas, Professor of study using endoscopic ultrasound Orofacial Surgery, Mainz Principal investigator(s) P. H. Kann Summary Ex vivo study to characterize mechanical Summary This study addresses adrenal masses properties of bone tissue by ultrasound to determine detected incidentally characterized as hormonally appropriate diagnostic procedures to plan surgical inactive or subclinical Cushing’s Syndrome not strategies in orofacial surgery requiring surgical treatment in a follow-up period up Funded by funded by IGEA Italy 1998-2002, at this to 15 years using endoscopic ultrasound. time not funded Project period 1998 – 2014
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Title Diagnostic and therapy of the primary Most important publications hyperaldosteronism Uitz PM, Hartleb S, Schaefer S, AL-Fakhri N, Kann PH Principal investigator(s) P. H. Kann (2013) Pituitary function in patients with hereditary Summary Diagnostic study to establish appropriate haemochromatosis. Horm Metab Res 45: 54-61 diagnostic strategies to identify patients with primary hyperaldosteronism which may be treated Lopez CL, Falconi M, Waldmann J, Boninsegna L, causally by minimal-invasive resection of a Conn’s Fendrich V, Goretzki PK, Langer P, Kann PH, Partelli adenoma. This study focuses on the role of S, Bartsch DK (2013) Partial pancreatico- endoscopic ultrasound of the adrenals. duodenectomy can provide cure for duodenal gastrinoma associated with multiple endocrine Title The value of different imaging techniques neoplasia type 1. Ann Surg 257: 308-314 including endoscopic ultrasound in the diagnosis of primary hyperaldosteronism Unger MM, Ekmann R, Björklund AK, Karlsson G, Principal investigator(s) P. H. Kann Andersson C, Mankel K, Bohne K, Tebbe JJ, Stiasny- Summary Patients with primary hyperaldosteronism Kolster K, Möller JC Mayer G, Kann PH, Oertel WH are studied, including the performance of different (2013) Unimpaired postprandial pancreatic imaging techniques like magnetic resonance imaging polypeptide secretion in Parkinson’s disease and (MRI), computed tomography (CT) and endoscopic REM sleep behaviour disorder. Mov Disord 28: 529- ultrasound. A lot of patients had undergone adrenal 533 vein sampling (AVS).The aim of the study is to compare these examination methods and to Bartsch DK, Albers M, Knoop R, Kann PH, Fendrich V, evaluate the therapeutic impact of adrenalectomy Waldmann J (2013) Enucleation and limited and antimineralocorticoid treatment, respectively. pancreatic resection provide long-term cure für Therefore different clinical and laboratory insulinoma in multiple endocrine neoplasia typ 1. parameters are investigated. Neuroendocrinology 98: 290-298
Title Long-term evaluation of adrenal tumors Kann PH, Hadji P, Bergmann RS (2014) Principal investigator(s) P. H. Kann Pharmakogene Osteoporose jenseits von Kortison. Summary Using endoscopic Protonenpumpenhemmer, Glitazone, Diuretika. Z ultrasound,morphological characteristics of adrenal Rheumatol 73: 323-328 tumors are investigated. The objective of this study is to examine whether there is a tumor progression Hadji P, Kauka A, Ziller, M, Birkholz K, Baier M, Muth or a change of the endocrine status over time. M, Kann PH (2014) Effect of adjuvant endocrine Additionally numerous laboratory and clinical therapy on hormonal levels in premenopausal parameters are analyzed. women with breast cancer: the ProBONE II study. Breast Cancer Res Treat 144: 343-351 Title Lithium-induced, MEN1-associated and sporadic primary hyperparathyroidism. A Tamagno G, Fedtke K, Eidenmüller M, Geks J, comparative study Hamann A, Langer K, Kann PH (2014) The Principal investigator(s) P. H. Kann polymorphism of type 1 collagen (COL1A1) gene Summary This study addresses the prevalence and does not correlate with an increased risk of foot special clinical and prognostic characteristics of ulcers in patients with diabetes mellitus. Exp Clin Lithium-induced primary hyperparathyroidism. Endocrinol Diabetes 122: in press Funded by not funded Project period 2013 – 2016
Title Localisation of MEN1-associated pNETS in the General information about the institute ventral and dorsal origin of the pancreas Principal investigator(s) P. H. Kann Summary MEN1-associated pNETS do not seem to Research funding 1.965.917,42 € occur equally distributed in the ventral and dorsal origin of the pancreas. This study aims to quantify the regional incidence and prevalence. Contact Details: Funded by not funded Baldingerstr. 1, 35043 Marburg, Project period 2014 – 2016 Tel.:++49 (0) 6421-58 66460 Director: Professor Dr. Thomas Gress
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Department of Internal Medicine: Division of Hematology, Oncology and Immunology
Chair Professor A. Neubauer modulates drug sensitivity by interacting with a DNA-damage program that is p53 dependent and Research projects causes cellular differentiation, thereby leading to Title Genetics of drug resistance in cancer decrease of immature leukemia stem cells and Principal investigator(s) A. Neubauer & A. Burchert significant less relapses (Meyer et al, 2009; Summary Cancer is a major threat to human society Neubauer et al, 2008). Our project intended to study in industrialized countries. Only 50% of all cancers drug resistance in cancer cells by using a synthetic can be cured by local therapies such as surgery or lethal screen with cytarabine and daunorubicine radiation therapy. Current evidence supports the (drugs that are frequently used in the therapy of growing importance of systemic therapies even in AML). We took advantage of a DNA-repair siRNA cancers, which were curatively operated on (so- library, as drug resistance frequently is caused by a called adjuvant therapies). However, only a minority change in DNA-repair. To this end, we have used a of patients’ cancer is diagnosed at an advanced stage siRNA screening consisting of 437 siRNA probes where systemic therapies (i.e. chemotherapy and specific for DNA-repair genes and applied this to immunotherapy) are not expected to cure the U2OS osteosarcoma cells (as proposed, because patients, but primarily to prolong life or treat expression of siRNA libraries into AML cells is rather symptoms. Only a minority of cancers can be cured difficult). So far, we have identified several candidate in an advanced stage by chemotherapy. In addition, genes, which sensitize cells to cytarabine-treatment in recurrent cancers response to systemic when knocked-down. Some of these genes have chemotherapy is mainly poor. As a consequence, been implicated in drug resistance, and some are resistance to systemic therapy is one of the major also “druggable”. Currently, we are validating these problems in medical oncology. Most programs to candidate genes. We now want to analyze genes in influence primary or secondary resistance to human primary AML samples and correlate these chemotherapy have failed and not entered clinical data with clinical parameters. Our goal therefore is practice. Therefore, this proposal heads for a to overcome drug resistance in AML. Ultimately, detailed molecular understanding of resistance. To these data may lead to a more individualized AML discover new candidate genes, we will take therapy, resulting in better treatment outcome. advantage of functional RNA interference based sh- Funded by DFG, Clinical Research Group, KFO 210 - RNA libraries, which have been established in our Genetics of drug resistance in cancer groups. Drugs such as platinum, cytarabine as well as Funding period 2012 – 2015 (2. funding period) doxorubicine will be used to uncover novel genes and pathways responsible for resistance in leukemia, Summary Transregio TRR17 (Würzburg – Marburg) lung and pancreatic cancer. We will also use has the background that we are far from completely sophisticated cell sorting techniques to address the understanding the single mechanisms leading to question of in vivo resistance in leukemias. In malignant transformation. Oncogenic Ras, or other addition, we will work on already established proteins activating important signaling pathways resistance genes such as NFAT and p73. We believe mediated by Ras, plays a key role in transformation that this approach will lead to a better in many tumor cells. In TRR17 we sought to understanding of molecular pathways of resistance mechanistically understand how cancer – related in cancer and enable the development of new drugs perturbed signaling is influenced by Ras. There are influencing these pathways. three separated parts in this transregio: A) Signal Funded by DFG, Clinical Research Unit, KFO 210 Transduction through the Ras Pathway. The second Funding period 2012 – 2016 (2. funding period) part tries to discern how cells respond to oncogenic Ras: Cellular Responses to Ras and their Genetic Title A synthetic lethal screen to identify novel Control. The third is translational and asks how Ras targets for therapy in acute myeloid leukemia modulates response e.g. to certain Principal investigator(s) A. Neubauer chemotherapeutic drugs: Ras-dependent signalling Summary Acute myeloid leukemia (AML) is a model in Human Tumors. disease in cancer research. As in other cancer types, Funded by DFG, SFB/Transregio 17 – German most AML patients still die of their disease, most Research Foundation, Transregional Collaborative frequently because of drug resistance. In our Research Centre 17: Ras-dependent pathways in previous work we have shown that oncogenic RAS human cancer
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Funding period 2008 – 2012, Final period 2012 – help us to better understand the role Ski plays in 2014 normal and malignant hematopoiesis. Project C2 Cooperation of Ras induced signaling and Funded by DFG – German Research Foundation, Priority Programme SPP 1463: Epigenetics in myeloid the nuclear oncogene Ski in acute myeloid leukemia neoplasias (AML) and malignant melanoma Funding period 2012 – 2015 Principal investigator(s) A. Neubauer, U.-M. Bauer & C. Brendel Title Signaling in persisting leukemic stem cells in Summary Part 1: We ask the following questions: acute myeloid leukemia 1. What is the relationship between DNA-damage Principal investigator (s) C. Brendel checkpoints and the differentiation observed Funded by DFG, KFO210 – German Science after activation the Ras-pathway? Foundation, Clinical Research Unit KFO 210 2. Is p53 needed in this differentiation program? Funding period 2012 – 2014 3. What role do repair enzymes play in this respect? We have recently published our main observations Title Immunmodulation und experimentelle (Meyer et al, 2009; Neubauer et al, 2008) and Therapie der bakteriellen Pneumonie durch concentrate now on part 2 of the project, Ski. mesenchymale Stammzellen Summary Part 2: Ski and Ras in AML Principal investigator (s) C. Brendel By performing gene array analyses in AML, we Funded by UGMLC – Universities of Giessen and discovered the nuclear repressor protein Ski as up- Marburg Lung Center, SFB/TR22 – Transregional regulated in AML, especially in AML with -7 / del7q. Collaborative Research Centre 22, Project 12 Interestingly, Ski and Ras were the two most up- Funding period 2012 – 2013 regulated genes in In this paper, we also have shown that Ski represses retinoic acid signaling in AML Title Interaction of pro-inflammatory signals in (Ritter et al, 2006). Recently we showed that micro- gastric MALT-Lymphomas RNA miR-29a regulates Ski on a post-transcriptional Principal investigator (s) A. Neubauer level (Teichler et al, 2011). The project now aims to Funded by LOEWE – Graduate School: Tumor and better understand the molecular interactions Inflammation between Ras signal transduction and Ski using a Funding period 2008 – 2013 mouse model. To this end we will collaborate with Prof. Zuber of Vienna. In this model we will try to analyse the oncogenic cooperativity between FLT3- Most important publications ITD (activating Ras-signaling) and Ski. Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, Schaich M, Ottmann O, Duyster J, Title Vitamin A-Resistenz in der akuten myeloischen Wandt H, Fischer T, Giagounidis A, Neubauer A, Leukämie: Die Rolle des nukleären Repressors Ski Reichle A, Aulitzky W, Noppeney R, Blau I, Kunzmann und funktionelle shRNA Barcode Sreens in V, Stuhlmann R, Kra¨mer A, Kreuzer K-A, Brandts C, myeloischen Zellen im Verbundvorhaben „Akute Steffen B, Thiede C, Müller-Tidow C, Ehninger G, Leukämie“ Berdel WE (2013) Sorafenib in combination with Principal investigators (s) A. Neubauer intensive chemotherapy in elderly patients with Summary This project will be ending in 2013. Several acute myeloid leukemia: results from a randomized, papers have been published (Metzelder et al, 2009; placebo-controlled trial. J Clin Oncol 31(25):3110-8 Teichler et al, 2011; Teichler et al, 2008). Funded by NGFN-plus Verbund: Akute Leukämien Schaich M, Parmentier S, Kramer M, Illmer T, Stölzel (Deutsches Zentrum für Luft- und Raumfahrt e.V., F, Röllig C, Thiede C, Hänel M, Schäfer-Eckart K, Projektträger für das BMBF) Aulitzky W, Einsele H, Ho AD, Serve H, Berdel WE, Funding period 2008 – 2013 Mayer J, Schmitz N, Krause SW, Neubauer A, Baldus CD, Schetelig J, Bornhäuser M, Ehninger G (2013) Title Epigenetics of the nuclear oncogene Ski in AML High-dose cytarabine consolidation with or without Principal investigator (s) A. Neubauer, additional amsacrine and mitoxantrone in acute Summary In this DFG program we are currently myeloid leukemia: results of the prospective investigating the epigenetic role of Ski in randomized AML2003 trial. J Clin Oncol 31(17): leukemogenesis. Specifically, we are interested 2094-102 which genes are regulated in leukemic transformation by the nuclear repressor Ski. We Hoffmann JC, Stabla K, Burchert A, Volkmann T, perform ChIP – Seq on a genome wide level and are Bornhäuser M, Thiede C, Neubauer A, Brendel C currently validating some of the genes. Also, we try (2014) Monitoring of acute myeloid leukemia to correlate these findings with expression data patients after allogeneic stem cell transplantation obtained in leukemia cells. This project will hopefully
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Clinical Institutions employing semi-automated CD34+ donor cell and thus enable persistence in CML. Secondly, we chimerism analysis. Ann Hematol 93(2):279-85 will study the hypothesis that IFN amplifies via induction of IRF8 sensing of oncogenic stress signals Huynh MQ, Goßmann J, Gattenlöehner S, Klapper W, initiated by BCR-ABL. Wacker HH, Ramaswamy A, Bittner A, Kaiser U, Funded by DFG, Clinical Research Group – KFO 210 Neubauer A (2014) Expression and pro-survival Genetics of drug resistance in cancer, TP 1 function of phospholipase Cγ2 in diffuse large B-cell Funding period 2008 – 2015 (second funding period) lymphoma. Leuk Lymphoma 2014 Sep 8:1-8. [Epub ahead of print] Title Functional genomic analysis of Sorafenib resistance in human FLT3-ITD-positive AML, Hanfstein B, Lauseker M, Hehlmann R, Saussele S, Principal investigators (s) A. Burchert Erben P, Dietz C, Fabarius A, Proetel U, Schnittger S, Summary Mechanism of Sorafenib resistance will be Haferlach C, Krause SW, Schubert J, Einsele H, Hänel studied. M, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Funded by DFG, Clinical Research Group – KFO 210 Stegelmann F, Pfreundschuh M, Waller CF, Genetics of drug resistance in cancer, TP 7 Spiekermann K, Baerlocher GM, Pfirrmann M, Funding period 2013 – 2017 (second funding period) Hasford J, Hofmann WK, Hochhaus A, Müller MC; SAKK and the German CML Study Group (2014) Title Studium eines neuen Imatinib- Distinct characteristics of e13a2 versus e14a2 BCR- Persistenzmodells bei der chronischen myeloischen ABL1 driven chronic myeloid leukemia under first- Leukämie DJCLS R 09/04 line therapy with imatinib. Haematologica Principal investigators (s) A. Burchert 99(9):1441-7 Funded by Deutsche José Carreras-Leukämie- Stiftung e. V. Hanfstein B, Shlyakhto V, Lauseker M, Hehlmann R, Funding period 2009 – 2013 Saussele S, Dietz C, Erben P, Fabarius A, Proetel U, Schnittger S, Krause SW, Schubert J, Einsele H, Hänel Title Rolle des Transkriptionsfaktors NFATc1 in der M, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Leukämogenese und Therapieresistenz der FLT3-ITD- Stegelmann F, Pfreundschuh M, Waller CF, positiven akuten myeloischen Leukämie DJCLS R Spiekermann K, Baerlocher GM, Pfirrmann M, 12/12 Hasford J, Hofmann WK, Hochhaus A, Müller MC Principal investigators (s) A. Burchert (2014) SAKK and the German CML Study Group. Funded by Deutsche José Carreras-Leukämie- Velocity of early BCR-ABL transcript elimination as an Stiftung e. V. optimized predictor of outcome in chronic myeloid Funding period 2013 – 2016 leukemia (CML) patients in chronic phase on treatment with imatinib. Leukemia 28(10):1988-92 Title Identifikation von Prädiktoren von CML Persistenz vor und nach Pausieren einer TKI / Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Interferon alpha Kombinationstherapie bei Fabarius A, Schreiber A, Proetel U, Pletsch N, chronischer myeloischer Leukämie DJCLS R 14/07 Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Principal investigators (s) A. Burchert Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Funded by Deutsche José Carreras-Leukämie- Stegelmann F, Pfreundschuh M, Waller CF, Stiftung e. V. Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Funding period 2014 – 2017 Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, Hochhaus A (2014) Deep Title Isolation and genetic analysis of individual molecular response is reached by the majority of persisting clones in CML: Role of Jak2 signaling for patients treated with imatinib, predicts survival, and survival is achieved more quickly by optimized high-dose Principal investigators (s) A. Burchert imatinib: results from the randomized CML-study IV. Funded by UKGM, University Medical Centre Giessen J Clin Oncol 32(5):415-23 / Marburg Funding period 2010 – 2013
Professor A. Burchert Title Elucidation of mechanisms of tumor stem cell drug resistance and persistence Title Modulation of the p19Arf-p53 tumor suppressor Principal investigators (s) A. Burchert response to overcome persistence in CML Summary shRNA screen in lung cancer and study of Principal investigators (s) A. Burchert resistance mechanisms in CML. Drug resistance in CML – It will be studied whether Funded by Behring-Röntgen Foundation BCR-ABL expression level control elicitation of the Funding period 2008 – 2013 p19Arf-p53-mediated tumor suppressive response,
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Title Interference of ICSBP deficiency with p53 patients after allogeneic stem cell transplantation function in the regulation of BCR/ABL induced employing semi-automated CD34+ donor cell transformation and kinase inhibitor resistance chimerism analysis. Ann Hematol 93(2):279-85 Principal investigators (s) A. Burchert Funded by DFG, SFB/TR 17 –German Research Foundation, Transregional Collaborative Research Professor T. Stiewe Centre 17: Ras-dependent pathways in human cancer, Project C2 Main fields of research Funding period 2008 – 2012, Final period 2012 – Cancer is caused by the accumulation and selection 2013 of genome mutations that disrupt tissue homeostasis resulting in uncontrolled cell proliferation. The most commonly mutated gene in Most important publications cancer patients is the p53 tumor suppressor gene, Hoffmann JC, Stabla K, Burchert A, Volkmann T which normally functions as a guardian of the (2013) Ann Hematol 93(2):279-85 Kröger N, Zabelina genome to prevent cancer development. Recently, T, Klyuchnikov E, Kropff M, Pflüger KH, Burchert A, two other genes – p63 and p73 – have been Stübig T, Wolschke C, Ayuk F, Hildebrandt Y, Bacher identified that are remarkably similar to p53. The U, Badbaran A, Schilling G, Hansen T, Atanackovic D, role of these genes in cancer development is yet Zander AR (2013) Toxicity-reduced, myeloablative unclear. Using classical molecular biology as well as allograft followed by lenalidomide maintenance as cutting-edge functional genomics we aim to salvage therapy for refractory/relapsed myeloma delineate the contribution of the p53 family genes to patients. Bone Marrow Transplant 48(3):403-7 cancer development, progression and therapy resistance and identify novel targets for cancer Hassan I, Brendel C, Zielke A, Burchert A, Danila R therapy. (2014) Immune regulatory plasmacytoid dendritic cells selectively accumulate in perithyroidal lymph Research projects nodes of patients with Graves disease: implications Title P73CANCER – p73 dependence in cancer: from for the understanding of autoimmunity. Rev Med molecular mechanisms to therapeutic targeting Chir Soc Med Nat Iasi 117(1):46-51 Principal investigator(s) T. Stiewe Summary Cancer cells frequently overexpress the Bornhäuser M, Thiede C, Neubauer A, Brendel C p73 gene suggesting that p73 is beneficial for tumor (2014) Monitoring of acute myeloid leukemia growth. Since p73 also has profound tumor patients after allogeneic stem cell transplantation suppressive functions, p73 overexpressing tumor employing semi-automated CD34+ donor cell cells are likely to be critically dependent on chimerism analysis. Ann Hematol 93(2):279-85 cooperating factors which keep the tumor suppressive function of p73 in check. It is the goal of Proetel U, Pletsch N, Lauseker M, Müller MC, this project to identify these essential survival Hanfstein B, Krause SW, Kalmanti L, Schreiber A, factors using high-throughput loss-of-function Heim D, Baerlocher GM, Hofmann WK, Lange E, screens as interesting novel targets for cancer Einsele H, Wernli M, Kremers S, Schlag R, Müller L, therapy. Hänel M, Link H, Hertenstein B, Pfirrman M, Funded by EU – European Research Council, FP7 ERC Hochhaus A, Hasford J, Hehlmann R, Saußele S; Starting Grant German Chronic Myeloid Leukemia Study Group; Funding period 2010 – 2015 Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) (2014) Older patients with Title Role of p53 core domain interactions for target chronic myeloid leukemia (≥65 years) profit more gene selection and tumor suppression from higher imatinib doses than younger patients: a Principal investigator(s) T. Stiewe subanalysis of the randomized CML-Study IV. Ann Summary The tumor suppressive transcription factor Hematol 93(7):1167-76 p53 limits the expansion of precancerous cells by inducing either cell-cycle arrest or apoptosis. The Burchert A (2014) Maintaining low BCR-ABL signaling mechanism by which the tetrameric p53 protein output to restrict CML progression and enable distinguishes functionally different target genes in persistence. Curr Hematol Malig Rep 9(1):9-16. this cell fate decision is only poorly understood. In Review this project we investigate p53 interactions within the p53 tetramer as a critical determinant of p53 Hoffmann JC, Stabla K, Burchert A, Volkmann T, functions in tumor suppression. Bornhäuser M, Thiede C, Neubauer A, Brendel C Funded by DFG, SFB/TR 17 – German Research (2014) Monitoring of acute myeloid leukemia Foundation, Transregional Collaborative Research
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Centre 17: Ras-dependent pathways in human induced chromatin changes to better understand cancer, Project B2 how Np73 contributes to epigenetic Funding period 2008 – 2013 reprogramming during tumorigenesis. Funded by DFG/SFB/TR 81 – German Research Title Role of DNA binding cooperativity for tumor Foundation, Transregional Collaborative Research suppression by p53 Centre: Chromatin changes in differentiation and Principal investigator(s) T. Stiewe malignancies; Project A10 Summary p53 acts as a tumor suppressor by Funding period 2010 – 2014, 2014 – 2018 inducing apoptosis in incipient cancer cells. We have shown previously in cell lines that cooperative DNA Title Role of the Myc/Miz1 interaction in the co- binding by p53 is required for its apoptotic function. operation of Ras and Myc Using a p53 cooperativity mutant mouse model we Principal investigator(s) M. Wanzel, H.-P. Elsässer & explore the functional role of DNA binding M. Eilers (Würzburg) cooperativity for tumor suppression in vivo. Funded by DFG, SFB/TR 17 – German Research Funded by DFG STI182/-1 – German Research Foundation, Transregional Collaborative Research Foundation Centre 17: Ras-dependent pathways in human Funding period 2013 – 2016 cancer Funding period 2008 – 2013 Title Role of p73 for drug resistance Principal investigator(s) T. Stiewe Title Gene Expression Profiling and Functional Summary Cancer cells frequently overexpress the Genomics p73 gene and this is clinically correlated with Principal investigator(s) M. Krause increased tumor aggressiveness and therapy Funding by DFG, SFB/TR 17 – German Research resistance leading to an inferior patient outcome. It Foundation, Transregional Collaborative Research is the goal of this project to understand in molecular Centre 17: Ras-dependent pathways in human terms how increased expression of p73 promotes cancer tumor progression to a drug resistant state. Funding period 2008 – 2013 Funded by DFG/KFO210, Clinical Research Group: Genetics of Drug Resistance in Cancer, Project B5 Title PhD program Molecular Cancer Biology Funding period 2008 – 2015 Principal investigator(s) T. Stiewe and S. Gaubatz Funded by DFG, SFB/TR 17 – German Research Title Exploring cancer therapies based on p53- Foundation, Transregional Collaborative Research reactivating drugs using shRNA barcode screening Centre 17: Ras-dependent pathways in human Principal investigator(s) M. Wanzel cancer, Project Z5 Summary Pharmacological inhibitors of the MDM2 Funding period 2008 – 2013 oncogene induce tumor cell death by reactivating the tumor suppressor p53. This project uses an RNAi Title Modulation of p53 DNA binding cooperativity screening approach to genetically pinpoint a subset for improved lung cancer therapy of cancer patients that profits from MDM2 inhibitor Principal investigator(s) T. Stiewe therapy. Funded by Deutsche Krebshilfe Funded by DFG/KFO210, Clinical Research Group: Funding period 2013 – 2016 Genetics of Drug Resistance in Cancer DFG/KFO210, Clinical Research Group: Genetics of Drug Resistance Title Role of the tumor suppressor p73 for B-cell in Cancer neoplasia Funding period 2012 – 2016 Principal investigator(s) T. Stiewe, C. Brendel & A. Rosenwald Title Mechanisms of gene silencing by the p53 family Funded by Deutsche José Carreras Leukämie inhibitor Np73 Foundation Principal investigator(s) T. Stiewe Funding period 2010 – 2014 Summary Transcription factors of the same gene family often bind to similar sequence motifs, yet can Title Genetic mechanisms of nutlin-resistance in generate opposite chromatin states. One example is acute myeloid leukemia the p53 family of tumor suppressors. Tumors Principal investigator(s) T. Stiewe & J. Cinatl frequently express the transcriptionally repressive (Frankfurt) p73 isoform Np73, which inhibits the Funded by Deutsche José Carreras Leukämie transactivating p53 family members and contributes Foundation to the establishment of a repressive chromatin Funding period 2012 – 2015 structure leading to reduced patient survival. In this project we characterize genome-wide Np73-
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Title Identification of p53-dependent tumor suppression pathways relevant for chemotherapy response in Acute Myeloid Leukemia (AML)
Principal investigator(s) O. Timofeev & T. Stiewe Funded by Deutsche José Carreras Leukämie Foundation Funding period 2014 – 2017
Most important publications Schlereth K, Heyl C, Krampitz AM, Mernberger M, Finkernagel F, Scharfe M, Jarek M, Leich E, Rosenwald A, Stiewe T (2013) Characterization of the p53 cistrome – DNA binding cooperativity dissects p53’s tumor suppressor functions. PLoS Genetics 9: e10003726
Maas AM, Bretz AC, Mack E, Stiewe T (2013) Targeting p73 in cancer. Cancer Letters 332: 229–236
Pribluda A, Elyada E, Wiener Z, Hamza H, Goldstein RE, Biton M, Burstain I, Morgenstern Y, Brachya G, Billauer H, Biton S, Snir-Alkalay I, Vucic C, Schlereth K, Mernberger M, Stiewe T, Oren M, Alitalo K, Pikarsky E, Ben-Neriah Y (2013) A senescence- inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell 24:242- 256
Timofeev O, Schlereth K, Wanzel M, Braun A, Nieswandt B, Pagenstecher A, Rosenwald A, Elsässer HP, Stiewe T (2013) p53 DNA Binding Cooperativity is Essential for Apoptosis and Tumor Suppression In vivo. Cell Reports 3: 1512-1525
Charles JP, Fuchs J, Hefter M, Vischedyk JB, Kleint M, Vogiatzi F, Schäfer JA, Nist A, Timofeev O, Wanzel M, Stiewe T (2014) Monitoring the dynamics of clonal tumour evolution in vivo using secreted luciferases. Nature Communications 5: e3981
General information about the institute
Research funding 3.016.423,95 €
Contact Details: Baldingerstrasse, 35043 Marburg, Phone:++49 (0) 6421-58 66273 Director: Professor Dr. Andreas Neubauer
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Department of Internal Medicine: Division of Cardiology
Chair Professor B. Schieffer Principal investigator(s) M. Schoppet, KT. Preissner Professor J. Schäfer (JLU Giessen) & E. Deindl (LMU München) Summary The transcription factor “early growth Main fields of research response-1 (Egr-1) is a crucial regulator of The major focus is the pathogenesis of arteriogenesis, which induces adhesion receptors atherosclerotic plaque development and associated and proteases. The upstream signal transduction of pathological remodeling in the vessel wall. The role arteriogenesis is incompletely understood. In a of cells and components of innate and adaptive murine model of arteriogenesis, which uses the immunity and their interaction with endothelial cells ligation of the femoral artery, the signaling cascades is of special interest. In this context, vascular leading to Egr-1 activation will be investigated. inflammation and its mediators (cells, cytokines and Funded by Behring-Röntgen Foundation chemokines) and their role in the formation of Funding period 2010 – 2013 atherosclerotic plaques are studied in animal models and patients with coronary heart disease. The aim is Title Inflammatory / familial dilated cardiomyopathy: to identify innovative therapeutic interventions for Is there a link to autoimmune diseases? - IKARIUS - interfering with plaque development, plaque Principal investigator(s) B. Schieffer & S. Pankuweit instability and vascular maladaptation. Summary The original aims of the project were: 1) The inclusion of patients within the cohort of the Research projects network with dilated cardiomyopathy (ejection fraction <45%, left ventricular enddiastolic diameter Title Impact of SOCS-1 on the differentiation status > 56mm) and in addition the 2) inclusion of all of Ly6Chigh- and Ly6Clow monocytes in an relevant data regarding a possible familial, infectious atherosclerotic mouse model or autoimmune etiology of the disease. This should Principal investigator(s) J. Schuett help us get for the first time data on the proportion Summary Within this fellowship the SOCS-1- of patients with sporadic or familial inflammatory or mediated impact on Ly6C-expression of monocytes not inflammatory DCM within the cohort of patients and its capacity to regulate monocyte differentiation with DCM. Derived from the data base, the biopsy is investigated. Based on the current knowledge it is and serum bank further aims of the project are 1) hypothesized that SOCS-1 influences gene the search for a genetic link to autoimmune diseases expression patterns on mRNA and miRNA levels and in patients with familial / inflammatory DCM and the thus regulates monocyte differentiation and that the 2) the search for a genetic predisposition for Ly6C-expression on monocytes is subjected to autoimmune diseases in patients with DCM, different classical pro-inflammatory as well as pro- especially inflammatory diseases. atherosclerotic stimuli. Funded by BMBF – Federal Ministry of Education Funded by DGK fellowship and Research Funding period 2014 – 20115 Funding period 2004 – 2017
Title Atherosclerosis and its consequence: From Title Clinical and prognostic relevance of beta1- proteomics and genomics towards optimized risk adrenoceptor autoantibodies in human heart stratification and invidualized prevention and disease: Etiology, Titer-Course, and Survival BetaAb- therapy – Bio-NRW HF (ETiCS) Principal investigator(s) B. Schieffer Principal investigator(s) B. Schieffer, S. Pankuweit & Summary Genetic and genomic characterization of R. Jahns, Würzburg patients with coronary artery diseases and their Summary The first aim is to clarify the affected relatives using 660W Infinium SNP chips and pathophysiological sequence of events leading to the HumanWG-6 v3.0 expression BeadChips in addition to identification of biological mechanisms generation of anti-beta1-Ab in humans by and key proteins using next generation sequencing. prospectively analyzing the potential links Funded by ISAS- Institute for analytical sciences between (a) acute myocardial inflammation or (b) Funding period 2012 – 2016 first acute myocardial ischemia and autoimmunity. The second goal is to Title Characterization of the expression and retrospectively determine the titer-course of activation of “early growth response-1 (Egr-1)” activating anti-beta1-Ab in large patient- signaling pathways in arteriogenesis in vivo populations with heart failure of known etiology compared with that in healthy subjects (a.
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Clinical Institutions idiopathic/inflammatory, b. ischemc cardio- Eberhard J, Grote K, Luchtefeld M, Heuer W, Schuett myopathy, and c. hypertensive heart disease H, Divchev D, Scherer R, Schmitz-Streit R, Langfeldt versus d. healthy controls). The final aim of both D, Stumpp N, Staufenbiel I, Schieffer B, Stiesch M studies is to evaluate the prognostic value of (2013) Experimental gingivitis induces systemic activating anti-beta1-Ab in heart failure inflammatory markers in young healthy individuals: a dependent on heart failure origin (a. single-subject interventional study. PLoS One idiopathic/inflammatory, b. ischemic 8(2):e55265 cardiomyopathy, c. hypertensive heart disease, d. healthy subjects). Lukasz A, Beutel G, Kümpers P, Denecke A, Westhoff- Bleck M, Schieffer B, Bauersachs J, Kielstein JT, Funded by BMBF – Federal Ministry of Education Tutarel O (2013) Angiopoietin-2 in adults with and Research congenital heart disease and heart failure. PLoS One Funding period 2009 – 2013 8(6):e66861
Title Effects of selective serotonin re-uptake Caforio AL, Pankuweit S, Arbustini E, Basso C, inhibition on MOrbidity, mOrtality and mood in Gimeno-Blanes J, Felix SB, Fu M, Heliö T, Heymans S, Depressed Heart Failure patients (MOOD-HF) Jahns R, Klingel K, Linhart A, Maisch B, McKenna W, Principal investigator(s) B. Schieffer, S. Pankuweit & Mogensen J, Pinto YM, Ristic A, Schultheiss HP, C. Angermann, Würzburg Seggewiss H, Tavazzi L, Thiene G, Yilmaz A, Charron Summary To investigate the effects of treatment P, Elliott PM; European Society of Cardiology with the SSRI escitalopram compared to placebo on Working Group on Myocardial and Pericardial morbidity and mortality in CHF patients with a Diseases (2013) Current state of knowledge on current episode of major depression. To estimate aetiology, diagnosis, management, and therapy of the improvement of depression by escitalopram myocarditis: a position statement of the European compared to placebo in depressed CHF patients. To Society of Cardiology Working Group on Myocardial assess whether possible reduction of morbidity and and Pericardial Diseases. Eur Heart J 34(33):2636-48 mortality (see primary objective) might be attributable to the improvement of depression. Grimm W, Timmesfeld N, Efimova (2013) ELeft Funded by BMBF – Federal Ministry of Education ventricular function improvement after prophylactic and Research implantable cardioverter-defibrillator implantation Funding period 2007 – 2013 in patients with non-ischaemic dilated
cardiomyopathy. Europace 15(11):1594-600
Dahms K, Sharkova Y, Heitland P, Pankuweit S, General information about the institute Schaefer JR (2014) Cobalt intoxication diagnosed with the help of Dr House. Lancet 383(9916):574 Research funding 836.294,14 € Meder B, Rühle F, Weis T, Homuth G, Keller A, Franke J, Peil B, Lorenzo Bermejo J, Frese K, Huge A, Witten A, Vogel B, Haas J, Völker U, Ernst F, Teumer Most important publications A, Ehlermann P, Zugck C, Friedrichs F, Kroemer H, Westhoff-Bleck M, Schieffer B, Tegtbur U, Meyer GP, Dörr M, Hoffmann W, Maisch B, Pankuweit S, Hoy L, Schaefer A, Tallone EM, Tutarel O, Mertins R, Ruppert V, Scheffold T, Kühl U, Schultheiss HP, Wilmink LM, Anker SD, Bauersachs J, Roentgen P Kreutz R, Ertl G, Angermann C, Charron P, Villard E, (2013) Aerobic training in adults after atrial switch Gary F, Isnard R, Komajda M, Lutz M, Meitinger T, procedure for transposition of the great arteries Sinner MF, Wichmann HE, Krawczak M, Ivandic B, improves exercise capacity without impairing Weichenhan D, Gelbrich G, El-Mokhtari NE, systemic right ventricular function. Int J Cardiol Schreiber S, Felix SB, Hasenfuß G, Pfeufer A, Hübner 170(1):24-9 N, Kääb S, Arbustini E, Rottbauer W, Frey N, Stoll M, Katus HA (2014) A genome-wide association study Grote K, Sonnenschein K, Kapopara PR, Hillmer A, identifies 6p21 as novel risk locus for dilated Grothusen C, Salguero G, Kotlarz D, Schuett H, cardiomyopathy. Eur Heart J 35(16):1069-77 Bavendiek U, Schieffer B (2013) Toll-like receptor 2/6 agonist macrophageConferences-activating lipopeptide -2 promotes reendothelialization and inhibits Contact Details: neointima formation after vascular injury. Baldingerstraße, 35043 Marburg, Arterioscler Thromb Vasc Biol 33(9):2097-104 Phone:++49 (0) 6421-58 66462
Director: Professor Dr. Bernhard Schieffer
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Department of Internal Medicine: Division of Pneumology
Chair Professor C. Vogelmeier Hyperproliferative Diseases of the Lung and Respiratory Tract" Main fields of research Principal investigator(s) W. Seeger (University of The main focus of clinical research is COPD. Various Giessen) & C. Vogelmeier groups in our institution work on either clinical Summary In this LOEWE Center the Justus Liebig aspects (e.g. drug effects, comorbidities, new University, the Philipps University Marburg and the therapies and diagnostic methods) or basic research Max Planck Institute for Heart and Lung Research related to these topics. (MPI) Bad Nauheim are participating. The goal is to Another important field is sleep medicine, as well as become an internationally leading center in the area emergency and intensive care medicine. The main of lung and respiratory tract disease by grouping the focus in these fields is related to clinical (e.g. experimental and clinical research in Giessen, ventilation procedures/techniques) and technical Marburg, and Bad Nauheim together. topics (biosignal analysis). Funded by Hessisches Ministerium für Wissenschaft In further projects markers of exhaled breath und Kunst (2010-2012) / Behring Röntgen condensate are analyzed. These projects try to Foundation (follow-up funding) answer, if diseases like COPD or Alzheimer can be Funding period 2010-ongoing diagnosed early with this simple technical procedure. Title DZL – German Center for Lung Research Principal investigator(s) W. Seeger (University of Research projects Giessen) & C. Vogelmeier Title COSYCONET (German COPD and Systemic Summary The German Center for Lung Research Consequences – Comorbidities Network) (DZL) is an association of the leading university and Principal investigator(s) C. Vogelmeier non-university institutions dedicated to lung Summary This huge multicenter cohort study aims research in Germany. Using translational research to build a national COPD cohort of 3000 patients, methods, the DZL seeks to jointly develop new which then serves as a basis for future studies. approaches for the prevention, diagnosis and Subprojects will characterize the patients over 18 therapy of serious lung diseases such as asthma, months, analyze the individual pattern of COPD, diffuse parenchymal lung disease or comorbidities, compare the data with other control pulmonary hypertension and lung cancer. cohorts and focus on specific clinically important Funded by BMBF – Federal Ministry of Education topics relevant for the progression of COPD. and Research Funded by BMBF – Federal Ministry of Education Funding period 2011-ongoing and Research Funding period 2009 – 2014 Title German central lab for the diagnosis of alpha-1 antitrypsin deficiency Title SFB Transregio 22 – Pulmonary Allergies Principal investigator(s) C. Vogelmeier, T. Greulich & Principal investigator(s) H. Renz (Institute of R. Koczulla Laboratory Medicine and Pathobiochemistry) & C. Summary We provide high level laboratory analysis Vogelmeier for the diagnosis of alpha-1 antitrypsin deficiency. In Summary Researchers from Marburg, Borstel and the last 9 years, 18.000 samples have been analyzed. Munich collaborate to use their unique competence Funded by Grifols in performing huge cross-sectional and longitudinal Funding period 2003 – 2013 cohort studies determining the risk factors for the development of allergies and asthma. Based on Title A Phase II/III, Double-Blind, Randomized, these studies the partners will develop a natural Placebo-Controlled, Multicenter, International Study scientific understanding of cellular and molecular Evaluating the Safety and Efficacy of Inhaled, mechanisms. Human, Alpha-1 Antitrypsin (AAT) in Alpha-1 Funded by DFG, SFB/TR 22 – German Research Antitrypsin Deficient Patients with Emphysema Foundation, Transregional Collaborative Research Principal investigator(s) C. Vogelmeier & T. Greulich Centre 22 Summary In this phase II/III clinical trial the safety Funding period 2005 – 2014 and efficacy of inhaled AAT is compared to placebo. We participate as one of two German centers in the Title LOEWE Center "UGMLC - Universities of German sub-study where the IMP is in addition to Giessen and Marburg Lung Center: Inflammatory and intravenous augmentation therapy with alpha-1 antitrypsin, making this population unique.
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Funded by Kamada Ltd. Funding period 2008 – ongoing Funding period 2010-ongoing Title Telemonitoring in patients with COPD - Title Comparison Of An Individualized Outpatient TeleTherapeut Exercise Training Versus A Standardized Outpatient Principal investigator(s) U. Koehler Exercise Training In Patients With Moderate To Very Summary The project aims to improve medical care Severe Chronic Obstructive Pulmonary Disease of patients with chronic obstructive lung disease Principal investigator(s) A.R. Koczulla & T. Greulich (COPD). A system will be developed that Summary The purpose of this study is to compare incorporates different signals like heart rate, the effects of different outpatient exercise training oxygenation, lung sounds and pulse transit time. programs in COPD patients. Patients will be trained Another system will be developed for instruction and for 3 – 5 months. Extensive assessment (including monitoring of patients training measures. exercise testing, muscle strength, inflammatory Funded by Hessenagentur LOEWE III markers) are performed before and after the Funding period 2012 – 2014 program. Funded by GlaxoSmithKline Title Discriminating factors for assessment of Funding period 2011 – 2013 daytime sleepiness in patients with obstructive sleep apnea and obesity Title Extracellular Matrix in patients with COPD Principal investigator(s) U. Koehler Principal investigator(s) C. Vogelmeier Summary The project aims to determine, how obese Summary Pilot study to investigate the changes of patients with obstructive sleep apnea (OSA) and extracellular matrix in patients with COPD. daytime sleepiness differ from obese patients with Funded by LOEWE Centre UGMLC – Universities of OSA without daytime sleepiness. Giessen and Marburg Lung Center Funded by Reinhard Löwenstein Foundation Funding period 2010-ongoing Funding period 2012 – 2014
Title INHALE Title ENCORE: Effects of Neupro on Cardiovascular Principal investigator(s) C. Vogelmeier Observations in Patients with Restless Legs Summary This study investigates the effect of the Syndrome LABA application with AKITA inhalation system in Principal investigator(s) U. Koehler patients with serve asthma. Summary Multicenter, double-blind, placebo- Funded by LOEWE Centre UGMLC – Universities of controlled, two-arm, randomized, parallel, treatment Giessen and Marburg Lung Center intervention, sleep lab phase IV study to assess the Funding period 2010-ongoing effect of rotigotine on nocturnal blood pressure in patients with idiopathic restless legs syndrome. Title Effect of Roflumilast on Exacerbation Rate in Funded by UCB Biosciences Patients With COPD Treated With Fixed Funding period 2011 – 2013 Combinations of LABA and ICS. A 52-week, Randomised Double-blind Trial With Roflumilast 500 Title Effects of Neupro on PLMs in Patients with µg Versus Placebo. The REACT Trial secondary Restless Legs Syndrome Principal investigator(s) C. Vogelmeier Principal investigator(s) U. Koehler Summary The REACT trial is a 52-week, randomised, Summary A multi-center, randomized, double-blind, double-blind, multi-centre study which investigates placebo-controlled, parallel-group polysomnography roflumilast when used in patients concomitantly study to investigate safety and efficacy of the treated with fixed combination treatment or triple rotigotine transdermal patch in subjects with restless therapy. legs syndrome and end-stage renal disease requiring Funded by Nycomed: A Takeda Company hemodialysis. Funding period 2010 – 2014 Funded by UCB Biosciences Funding period 2011 – 2013 Title Serve-HF Principal investigator(s) U. Koehler Title REFRESH-PD: Randomized evaluation for Summary The purpose of this trial is to evaluate the rotigotine’s efficacy in sleep in idiopathic PD patients long-term effects and cost-effectiveness of adaptive Principal investigator(s) U. Koehler servo-ventilation on the mortality and morbidity of Summary A multi-center, randomized, double-blind, patients with stable heart failure due to left placebo-controlled study to evaluate the effects of ventricular systolic dysfunction, already receiving rotigotine on sleep efficiency in patients with optimal medical therapy, who have sleep disordered advanced Parkinson’s disease. breathing (SDB) that is predominantly central. Funded by UCB Celltech Funded by ResMed GmbH & Co.KG, München Funding period 2011 – 2013
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Title Support for MPG-approval of a product for Summary Increasing development and application of precise detection of body position inhalable carbon nanoparticles (CBNP) bears the risk Principal investigator(s) U. Koehler of toxicity, especially on the lung. However long Summary In this project the system of IfM GmbH will term effects still are unknown and will be evaluated be prepared for MPG-approval. in this project. The overall aim is to study the Funded by Ingenieurbüro für Medizintechnik GmbH deleterious long term effects of CBNP on normal and (IfM) preinjured lungs. Funding period 2012 – 2013 Funded by BMBF – Federal Ministry of Education and Research Title Motivational influences on the results of Funding period 2014 – 2017 vigilance measurements Principal investigator(s) U. Koehler Title PostDoc Stipendium to Dr. Shashi Pavan Summary In this project the motivational influences Chillappagari on the results of vigilance measurements are Principal investigator(s) M. Henke determined. Summary Cystic fibrosis leads to compromised Funded by Reinhard Löwenstein Foundation congenital and adaptive immune reactions of the Funding period 2013 – 2014 respiratory epithelium due to reduced expression of TLR-4 on the cell surface. This is likely to be relevant Title Development of an algorithm to detect Cheyne- for the chronic inflammation of the airways. Stokes breathing patterns in patients with chronic Funded by LOEWE – ECCPS heart failure Funding period 2010 – 2013 Principal investigator(s) U. Koehler Summary In this project an algorithm will be Title AST@home development to detect Cheyne-Stokes breathing Principal investigator(s) A. R. Koczulla patterns out of PSG-data. Summary In this project a COPD Exacerbation will be Funded by Ingenieurbüro für Medizintechnik GmbH developed. (IfM) Funded by LOEWE III Funding period 2013 – 2014 Funding period 2014 – 2016
Title Validation and optimization of an algorithm to Title Effects of Prolastin® therapy on peripheral detect Cheyne-Stokes breathing pattern blood monocyte populations Principal investigator(s) U. Koehler Principal investigator(s) A. R. Koczulla & S. Summary In this project a developed algorithm to Janciauskiene (MHH) detect Cheyne-Stokes breathing pattern will be Summary In this project the augmentation of AAT validated and optimized. and its function on neutrophil and macrophage Funded by Ingenieurbüro für Medizintechnik GmbH regulation in AAT and COPD patients and samples (IfM) will be evaluated. Funding period 2014 ongoing Funded by Grifols Funding period 2014 – 2016 Title Toxicology of Carbon Black Nanoparticles (CBNP) on Type II Pneumocytes and Clara Cells Principal investigator(s) B. Müller Summary Increasing development and application of General information about the institute carbon nanoparticles bears the risk of toxicity, especially upon inhalation. Depending on CBNP Research funding 3.928.839,96 € characteristics the project aims to evaluate the pathomechanisms of impairment of surfactant- and antioxidant-metabolism as well as inflammation in type II pneumocytes and the clara cells. The overall Most important publications aim is to categorize CBNP characteristics and their Kratzer A, Salys J, Nold-Petry C, Cool C, Zamora M, corresponding toxicologic potential. Bowler R, Koczulla AR, Janciauskiene S, Edwards MG, Funded by BMBF – Federal Ministry of Education Dinarello CA, Taraseviciene-Stewart L (2013) Role of and Research IL-18 in second-hand smoke-induced emphysema. Funding period 2010 – 2013 Am J Respir Cell Mol Biol 48(6): 725-732 Title Long Term Toxicology of Modified Carbon Black Nanoparticles (CBNP) on Normal and Preinjured Greulich T, Hattesohl A, Grabisch A, Koepke J, Lungs (NanoCOLT) Schmid S, Noeske S, Nell C, Wencker M, Jörres RA, Principal investigator(s) B. Müller Vogelmeier CF, Köhler U, Koczulla AR (2013)
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Detection of obstructive sleep apnoea by an electronic nose. Eur Respir J 42(1): 145-155
Hoogendoorn M, Al MJ, Beeh KM, Bowles D, Graf von der Schulenburg JM, Lungershausen J, Monz BU, Schmidt H, Vogelmeier C, Rutten-van Mölken MP (2013) Cost-effectiveness of tiotropium versus salmeterol: the POET-COPD trial. Eur Respir J 41(3): 556-564
Alter P, Luetteken L, Nell C, Haid D, Kehr K, Greulich T, Apelt S, Langenhan K, Hohmann C, Vogelmeier CF, Koczulla AR (2014) Exercise training leads to physiological left ventricular hypertrophy in COPD. Int J Cardiol 174(1): 156-157
Grimm W, Hildebrandt O, Nell C, Koehler U (2014) Excessive daytime sleepiness and central sleep apnea in patients with stable heart failure. Int J Cardiol 176(3): 1447-1448
Kill C, Hahn O, Dietz F, Neuhaus C, Schwarz S, Mahling R, Wallot P, Jerrentrup A, Steinfeldt T, Wulf H, Dersch W (2014) Mechanical ventilation during cardiopulmonary resuscitation with intermittent positive-pressure ventilation, bilevel ventilation, or chest compression synchronized ventilation in a pig model. Crit Care Med 42(2): e89-95
Frenzel E, Wrenger S, Immenschuh S, Koczulla R, Mahadeva R, Deeg HJ, Dinarello CA, Welte T, Marcondes AM, Janciauskiene S (2014) Acute-phase protein α1-antitrypsin--a novel regulator of angiopoietin-like protein 4 transcription and secretion. J Immunol 192(11): 5354-5362
Rogosch T, Herrmann N, Maier RF, Domann E, Hattesohl A, Koczulla AR, Zemlin M (2014) Detection of bloodstream infections and prediction of bronchopulmonary dysplasia in preterm neonates with an electronic nose. J Pediatr 165(3): 622-624
Contact Details: Baldingerstraße, 35043 Marburg, Phone: +49 (0) 6421-58 66451 Director: Professor Dr. Claus Vogelmeier
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Department of Internal Medicine: Division of Psychosomatic Medicine and Psychotherapy
Chair Professor J. Kruse medical assessment of refuges with PTSD in legal residence procedures. Main fields of research Funded by VW Foundation Psychotherapy / Psychosomatic interventions for Funded period 2009 – 2013 chronic physical illnesses with mental co-morbidity, especially in diabetology, oncology, cardiology, and Title The psychosomatic / psychotherapeutic care in neurology. Psychosomatic treatment of somatoform health insured care in Germany disorders, especially somatoform pain disorders, Principal investigator(s) J. Kruse psychotherapy of posttraumatic stress disorders as a Summary The study aims: result of extreme traumatic incidents (abuse, a) to describe the current reality of care in violence), the effects of chronic stress experiences outpatient psychosomatic / psychotherapeutic and extreme violence experienced in childhood and care adulthood on the development of chronic physical b) to examine the different areas of care by illnesses, including the psychoneuroimmunologic psychotherapeutic / psychosomatic physicians changes, Health Care Research. and psychologists c) and to analyse the differential effectiveness / Research projects efficiency of these structures Title Randomized controlled study to investigate Funded by Kassenärztliche Bundesvereinigung effect mechanisms of EMDR (Eye Movement Funded period 2010 – 2014 Desensitization and Reprocessing) treatment Principal investigator(s) M. Sack, J. Kruse Title Integrated psychosocial treatment program for Summary The effect mechanisms of EMDR patients with type 2 diabetes (psy-PAD) - Evaluation treatment are examined within the context of an of an interdisciplinary psychosocial care model RCT in patients with uncomplicated PTSD. The Principal investigator(s) J. Kruse standard protocol is compared with a simple focus Summary The aim of the project is the on attention and the narration of trauma. implementation and evaluation of an integrated Funded by DFG – German Research Foundation collaborative care (psy-PAD), which is conducted by Funding period 2010 – 2013 a consulting psychotherapist in specialized diabetic outpatient clinics in cooperation with the Title The course of mental disorders and their diabetologist. predictors Funded by Bundesärztekammer Principal investigator(s) J. Kruse, F. Leichsenring Funded period 2010 – 2014 Summary Based on a systematic literature analysis, the project aims to determine the current scientific Title Chronic stress, anxiety and diabetes – The level of knowledge on the course of mental disorders impact of chronic psychological distress on the onset and relevant factors. It shall also be studied which and course of Type 2 Diabetes (DIAMANT-CAD) influence psychotherapy is having on the long-term Principal investigator(s) J. Kruse, K.H. Ladwig course of mental disorder. Summary Based on population-based data from Funded by Dr. Karl Wilder Foundation cross sectional and prospective studies within the Funded period 2010 – 2013 MONICA/KORA research platform, the project aims (a) to describe the prevalence of anxiety, Title The return of torture? – An interdisciplinary posttraumatic stress disorder (PTSD) in subjects with study on an extreme form of violence, its media normal glucose metabolism, pre-diabetes and type 2 representation, and its ostracism diabetes (T2DM), (b) to study the synergistic effect Principal investigator(s) J. Kruse, C. Altenhain & G. sizes of adverse sub-threshold psychosocial Görling conditions to predict subsequent onset of T2DM, as Summary The aim is a) to examine in systematic well as onset of complications and mortality in reviews the effects of extreme violence on health, b) previously diabetic individuals (c), to establish an to clarify historically how psychotherapy and allostatic load model to estimate the effect size of psychosomatics handled the issue of extreme psycho-biological and behavioural mechanisms on violence experience and c) to analyse the current T2DM onset, complications onset, and mortality. Funded by BMBF – Federal Ministry of Education and Research: Kompetenznetz Diabetes
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Funded period 2011 – 2014 sectional study with 2970 participants. J Psychosom Title Effectiveness of a step care approach for Res 74(4):340-5 diabetic patients with subthreshold depression, Peters EM, Liezmann C, Spatz K, Ungethüm U, diabetes related distress and/or poor glycemic Kuban RJ, Daniltchenko M, Kruse J, Imfeld D, Klapp control BF, Campiche R (2013) Profiling mRNA of the Principal investigator(s) B. Kulzer, J. Kruse Graying Human Hair Follicle Constitutes a Promising Summary The overall objective of this study is to State-of—the-Art Tool to Assess its Aging: An develop a step care approach and evaluate the Exemplary Report. J Invest Dermatology 133: 1150- effectiveness of such a step care approach versus a 1160 treatment as usual in diabetic patients with poor glycemic control and elevated depressive symptoms Huth C, Thorand B, Baumert J, Kruse J, Emeny RT, or specific diabetes related stress in a randomised Schneider A, Meisinger C, Ladwig KH (2014) Job controlled trial. strain as a risk factor for the onset of type 2 Funded by BMBF – Federal Ministry of Education diabetes mellitus: findings from the MONICA/KORA and Research: Kompetenznetz Diabetes Augsburg cohort study. Psychosom Med 76(7):562-8 Funded period 2011 – 2014 Contact Details: Baldingerstraße, 35043 Marburg Most important publications Tel.:++49 (0) 6421-58 64012 Baumert J, Lukaschek K, Kruse J, Emeny RT, Koenig Director: Professor Dr. Johannes Kruse W, von Känel R, Ladwig KH; KORA investigators (2013) No evidence for an association of posttraumatic stress disorder with circulating levels of CRP and IL-18 in a population-based study. Cytokine 2013;63(2):201-8
Hofmann M, Hagemeier I, Altenhain K, Kruse J (2013) Evaluation ärztlicher und psychologischer Bescheinigungen in asyl- und aufenthaltsrechtlichen Verfahren. Psychother Psych Med DOI: 10.1055/s- 0033-1347254
Hofmann M, Köhler B, Leichsenring F, Kruse J (2013) Depression as a Risk Factor for Mortality in Individuals with Diabetes: A Meta-Analysis of Prospective Studies. Plos One 8(11)
Icks A, Albers B, Haastert B, Pechlivanis S, Bokhof B, Slomiany U, Erbel R, Jöckel KH, Kruse J, Nowotny B, Herder C, Giani G, Moebus S (2013) Diabetes incidence does not differ between subjects with and without high depressive symptoms – 5-year follow- up results of the Heinz Nixdorf Recall Study. Diabetic Medicine 30(1): 65-69
Kruse J, Larisch A, Hofmann M, Herzog W (2013) Ambulante psychosomatische und psychothera- peutische Versorgung in Deutschland – Versorgungsprofile abgebildet durch Daten der Kassenärztlichen Bundesvereinigung (KBV). Psychoth Psych Med 59: 254-272
Lukaschek K, Baumert J, Kruse J, Emeny RT, Lacruz ME, Huth C, Thorand B, Holle R, Rathmann W, Meisinger C, Ladwig KH; KORA Investigators (2013) Relationship between posttraumatic stress disorder and type 2 diabetes in a population-based cross-
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Department of Cardiovascular Surgery
Chair Professor R. Moosdorf element analysis. Indices for spatial heterogeneity Principal investigator Professor S. Vogt and systolic dyssynchrony were determined for healthy abdominal aortas and abdominal aneurysms. Main fields of research All examined aortic wall segments exhibited considerable heterogenous in-plane strain 1. Regulation of Respiration distributions. Higher spatial resolution of strain During evolution from prokaryotes to eukaryotes, imaging resulted in the detection of significantly the main function of cytochrome c oxidase (COX), higher local peak strains (p ≤ 0.01). In comparison i.e., the coupling of oxygen reduction to proton with healthy abdominal aortas, aneurysms showed translocation without the production of ROS reduced mean strains and increased spatial (reactive oxygen species) remained unchanged heterogeneity and more pronounced temporal demonstrating its robustness. A new regulation of dyssynchrony as well as delayed systole. Three- respiration by the ATP/ADP ratio was introduced in dimensional ultrasound speckle tracking enables the eukaryotes based on nucleotide interaction with the analysis of spatially highly resolved strain fields of added COX subunit IV. This allosteric ATP-inhibition the aortic wall and offers the potential to detect was proposed to keep the mitochondrial membrane local aortic wall motion deformations and potential (ΔΨ(m)) at low healthy values and thus abnormalities. These data allow the definition of prevents the formation of ROS at complexes I and III. new indices by which the different biomechanical ROS have been implicated in various degenerative properties of healthy aortas and aortic aneurysms diseases. The allosteric ATP-inhibition of COX is can be characterized. reversibly switched on and off by phosphorylation of COX at a serine or threonine. In more than 100 3. Calcification Studies in Arteriosclerosis individual preparations of rat heart and liver The knowledge available to the field of arterial mitochondria, prepared under identical conditions, calcification and vascular mineral metabolism has the extent of allosteric ATP-inhibition varied. This grown in the recent years. Our understanding of this variability correlates with the variable inhibition of disease biology has been enabled by incredible uncoupled respiration in intact isolated advancements in bone and mineral research that mitochondria by ATP. It is concluded that in higher occurred alongside innovative investigation in organisms the allosteric ATP-inhibition is continually cardiovascular medicine. As in bone, mechanistic switched on and off by neuronal signalling in order heterogeneity exists in the different forms of to change oxidative phosphorylation from optimal vascular mineral deposition. There is heterogeneity efficiency with lower rate of ATP synthesis under in the sources and mechanisms of mineralizing resting conditions (low ΔΨ(m) and ROS production) vascular cell types: osteochondrocytic VSMC to maximal rate of ATP synthesis under active transdifferentiation, VSMC apoptosis, and (working, stress) conditions (elevated ΔΨ(m) and osteochondrocytic lineage allocation of multipotent ROS production). mesenchymal cells all contribute but to varying extents dependent on pathophysiologic setting and 2. Strain Analysis of the Aortic Wall disease stage. It has been posited that marrow Aortic wall strains are indicators of biomechanical derived circulating osteoprogenitors may also changes of the aorta due to aging or progressing contribute to vascular mineralizing cell types. The pathologies such as aortic aneurysm. We knowledge about the ectopic bioapatite crystals is investigated the potential of time-resolved three- not complete, despite of well defined phase dimensional ultrasonography coupled with speckle- composition and general crystal chemical tracking algorithms and finite element analysis as a characteristics. novel method for noninvasive in vivo assessment of The aim of this study discribes a poven technique aortic wall strain. Three-dimensional volume and method of sample preparation for the datasets of 6 subjects without cardiovascular risk undisorted assessment of ultrastructural factors and 2 abdominal aortic aneurysms were characteristics in nanostructured calcified acquired with a commercial real time three- pathological deposits. The primary objective dimensional echocardiography system. Longitudinal comprimizes characterizing the structure of the and circumferential strains were computed offline calcification down to nanoscale in terms of with high spatial resolution using a customized composition, crystallography and grain size in an ex- commercial speckle-tracking software and finite vivo calcified coronary artery. An approach common
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Clinical Institutions to material science, but rather novel to life science, Most important publications was utilized. Electron Back Scatter Diffraction (EBSD) and Ramzan R, Weber P, Linne U, Vogt S (2013) GAPDH: Transmission Kikuchi Diffraction (TKD) analysis in the the missing link between glycolysis and scanning electron microsocope (SEM) were used, mitochondrial oxidative phosphorylation? Biochem just as well as elemental analysis (EDX) and Soc Trans 41(5):1294-7 viscoelastic mapping by AM-FM technique. The AM- FM technique provides stiffness or Young’s modulus Karatolios K, Wittek A, Nwe TH, Bihari P, Shelke A, maps of the sample surface along with topography Josef D, Schmitz-Rixen T, Geks J, Maisch B, Blase C, information. The vascular calcification was compared Moosdorf R, Vogt S (2013) Method for aortic wall to a trabecular bone sample as control. Similarities in strain measurement with three-dimensional chemistry were analysed but slightly differences in ultrasound speckle tracking and fitted finite element crystallography. analysis. Ann Thorac Surg 96(5):1664-71
Research projects Vogt S, Ramzan R, Weber P, Troitzsch D, Rhiel A, Title Study on different working states of the Sattler A, Irqsusi M, Ruppert V, Moosdorf R (2013) mitochondrial enzyme complex IV for understanding Ischemic preconditioning results in an ATP- ROS production in myocardial ischemia and dependent inhibition of cytochrome C oxidase. reperfusion Shock 40(5):407-13 Principal investigator(s) S. Vogt, R. Moosdorf, N. Mirow, A. Wittek, Ch. Blasé & R. Ramzan Kadenbach B, Ramzan R, Vogt S (2013) High Summary 1. efficiency versus maximal performance—the cause Funded by DFG – German Research Foundation, of oxidative stress in eukaryotes: a hypothesis. VO809/4-1 Mitochondrion 13(1):1-6 Funding period 2006 – 2013 Wittek A, Karatolios K, Bihari P, Schmitz-Rixen T, Title Aortic wall strain measurements with three- Moosdorf R, Vogt S, Blase C (2013) In vivo dimensional ultrasound speckle tracking and fitted determination of elastic properties of the human finite element analysis aorta based on 4D ultrasound data, in: J Mechanical Principal investigator(s) S. Vogt, R. Moosdorf, N. Behavior of Biomedical Materials 27: 167-83 Mirow, A. Wittek, Ch. Blasé & R. Ramzan Summary 2. Wittek A, Karatolios K, Vogt S, Moosdorf R, Schmitz- Funded by DFG – German Research Foundation, Rixen T, Blasé C (2013) Use of time resolved 3D VO809/4-1 ultrasound data for the determination of the Funding period 2006 – 2013 anisotropic elastic properties of the human aorta: Ultraschall in der Medizin 10/2013. 34, 1 Title Vascular Calcification Analysis: An approach common to material science, but rather novel to life science Contact Details: Principal investigator(s) S. Vogt, R. Moosdorf, N. Baldingerstraße, 35043 Marburg, Mirow, A. Wittek, Ch. Blasé & R. Ramzan Tel.:++49 (0) 6421-58 66223 Summary 3. Director: Professor Dr. Rainer Moosdorf Funded by BMBF – Federal Ministry of Education and Research, FKZ:01M3198D Funding period 2012 – 2016
General information about the institute
Research funding 185.055,73 €
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Clinical Institutions
Department of Neurosurgery
Chair Professor C. Nimsky optimized the scan protocol due to optimization of Head Lab Research Group: the reconstruction of the optic radiation several Professor J.-W. Bartsch acquisition schemes are tested and evaluated with respect to clinical constraints. Main fields of research Funded by UKGM – University Medical Centre Image processing & imaging analysis: Giessen / Marburg Funding period 2013 – 2015 Visualization of eloquent brain areas by using
state-of-the-art methods of neuronavigation and Title Screening of drug candidates for inhibition of intra-operative imaging, including MRI, fiber ADAM8 tractography, ultrasound, and confocal laser Prinicipal Investigator(s) J.-W. Bartsch endoscopy to optimize the extent of tumor Summary These proposals aim to identify novel resection with preservation of function candidate cyclic peptides for ADAM8 inhibition by Analysis of tumor properties and determination large-scale screen of phage display libraries. Novel of tumor grading using MR spectroscopy, peptides will be tested in preclinical phase studies. correlation imaging to histology Funded by Bicycle Therapeutics, Inc., Cambridge, UK Optimization of functional clinical MR imaging CRT/Medivir protocols and analysis strategies for Funding period 2012 – 2013 intraoperative use
Imaging of tumor pattern and tumor growth in Title A randomized, double-blinded and placebo- glioma mouse models controlled phase 3 study to investigate the efficacy
and the safety of progesterone in patients with Molecular/Cell Biology: traumatic brain injury (TBI) Identification of proteolytic processes for growth Prinicipal Investigator(s) Ch. Nimsky and invasiveness of tumor cells Summary SyNAPSe is a global, Phase 3, multi-center Mechanisms of chemoresistance in gliomas pivotal trial to evaluate the effectiveness of BHR- Rational design of specific protease inhibitors as 100, a proprietary progesterone formulation, in anti-tumor drugs treating severe Traumatic Brain Injury (TBI). Previous Photodynamic therapy of gliomas clinical trials have shown that progesterone has neuroprotective properties for both males and Research projects females. Traumatic brain injury (TBI) is a major cause Title Tractography for visualization of fiber bundles of death and disability worldwide. Among TBI victims in the proximity of primary brain tumours injuries result from automobile crashes, sports Principal investigator(s) M. Bauer, D. Kuhnt & Ch. accidents, assaults and injuries sustained on the Nimsky battlefield. Summary This project aims to reliably visualize Funded by: BHR Pharma, LLC. subcortical fiber bundles as risk structures in the Funding period 2012 – 2013 proximity of gliomas with perifocal edema. This is important in the context of maximum safe tumor Title Development of a concept for combined resection without new postoperative neurological intraoperative multimodal spectroscopy with digital deficits, which serves as positive predictive factor for image processing for resection of malignant Gliomas extended patient survival, within the inter- Prinicpal Investigator(s) F. Duffner, R. Kessler, R. Ritz disciplinary concept combining microsurgery, & J.W. Bartsch multimodal navigation, intraoperative imaging, Summary This project aims to use fluorescence, radiation, and chemotherapy. UV/VIS and s-NIR absorption spectroscopy to Funded by Behring-Röntgen Foundation No. 58-0044 visualize malignant tumor tissue. Multidimensional Funding period 2011 – 2013 absorptions spectra can be acquired and combined with complex data analysis to provide reliable Title Optimizing intraoperative visualization of the prediction of tumor grading. optic radiation for neurosurgical interventions Funded by: Baden-Württemberg Foundation Principal investigator(s) D. Kuhnt & M. Bauer Funding period: 2013 – 2014 Summary This project aims to improve the visualization of the optic radiation which is heavily Title Validation of the metalloprotease ADAM8 as influenced by the MRI acquisition protocol. To biomarker in primary tumors and metastases
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Clinical Institutions
Prinicipal Investigator(s) C. Conrad & J.W. Bartsch progesterone for severe traumatic brain injury. N Summary Malignant breast tumors are the most Engl J Med 371(26):2467-76 common incident form of cancer and cause of cancer-related death in women worldwide (IARC Brüssler J, Marxer E, Becker A, Schubert R, report, 2008). In this project, the role of the Schümmelfeder J, Nimsky C, Bakowsky U (2014) Metalloprotease ADAM8 is investigated to validate Correlation of structure and echogenicity of ADAM8 as a tumor target in malignant breast nanoscaled ultrasound contrast agents in vitro. tumors. Colloids Surf B Biointerfaces 117:206-15 Funded by Alfred und Ursula Kulemann Foundation Funding period 2013 Romagnoli M, Mineva ND, Polmear M, Conrad C, Srinivasan S, Loussouarn D, Barillé-Nion S, Title: Multimodal analysis of glioma growth in a Georgakoudi I, Dagg Á, McDermott EW, Duffy MJ, mouse model McGowan PM, Schlomann U, Parsons M, Bartsch Prinicipal Investigator M. Bauer JW, Sonenshein GE (2014) ADAM8 expression in Summary The aim of this project is to establish invasive breast cancer promotes tumor multimodal methods (MR Imaging, biomarkers, dissemination and metastasis. EMBO Mol Med tracers) for the detection and analysis of tumor 6(2):278-94. growth, hypoxia, and angiogenesis in situ using a mouse model for gliomas. Noell S, Beschorner R, Bisdas S, Beyer U, Weber RG, Funded by Behring-Röntgen Foundation Fallier-Becker P, Ritz R (2014) Simultaneous Funding period 2014 – 2016 subependymomas in monozygotic female twins: further evidence for acommon genetic or developmental disorder background. J Neurosurg 121(3):570-5 General information about the institute
Research funding 168.155,25 € Contact Details: Baldingerstraße, 35043 Marburg, Tel.: +49 (0) 6421-58 66447 Most important publications Director: Professor Dr. Christopher Nimsky
Bauer MH, Kuhnt D, Barbieri S, Klein J, Becker A,
Freisleben B, Hahn HK, Nimsky C (2013)
Reconstruction of white matter tracts via repeated deterministic streamline tracking--initial experience.
PLoS One 8(5):e63082
Egger J, Kapur T, Fedorov A, Pieper S, Miller JV,
Veeraraghavan H, Freisleben B, Golby AJ, Nimsky C,
Kikinis R (2013) GBM volumetry using the 3D Slicer medical image computing platform. Sci Rep3:1364
Kuhnt D, Bauer MH, Egger J, Richter M, Kapur T,
Sommer J, Merhof D, Nimsky C (2013) Fiber tractography based on diffusion tensor imaging compared with high-angular-resolution diffusion imaging with compressed sensing: initial experience.
Neurosurgery 72 Suppl 1:165-75
Tonge D, Zhu N, Lynham S, Leclere P, Snape A,
Brewer A, Schlomann U, Ferdous T, Tennyson C,
Bartsch JW, Ward M, Pizzey J (2013) Axonal growth towards Xenopus skin in vitro is mediated by matrix metalloproteinase activity. Eur J Neurosci 37(4):519-
31
Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, Nelson NR, Stocchetti N, SYNAPSE Trial Investigators (2014) A clinical trial of
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Clinical Institutions
Department of Orthopaedics and Rheumatology
Chair Professor S. Fuchs-Winkelmann doses Xeomin® (incobotulinumtoxin A, NT 201) for the treatment of lower limb spasticity in children Main fields of research and adolescents (age 2-17 years) with cerebral palsy The focus of the research group of the department Principal investigator C.-D. Peterlein of Orthopedics and Rheumatology is set on origin of Summary In this clinical study, the effect of musculoskeletal diseases as well as their treatment botulinum toxin injections in children and options. In this connection, both clinical issues as adolescents with cerebral palsy is examined. Main well as aspects of basic research were considered focus is set on spasticity, locomotion, and the and linked with each other. Therefore the impact of sensation of pain. commercial available tissue replacement materials Funded by Merz Pharmaceuticals GmbH (endoprothesis and biological transplants) on healing Funding period 2013 – 2016 and patient satisfaction as well as their application is analyzed and new scaffolds for bone and tendon Title Open-label, non-controlled, multicenter long- healing were developed. The research is term study to investigate the safety and efficacy of supplemented by analysis of various aspects of bone Xeomin® (incobotulinumtoxin A, NT 201) for the tumors with respect to their metastasis. treatment of spasticity of the lower limb(s) or of combined spasticity of upper and lower limb in Research projects children and adolescents (age 2-17 years) with Title Tissue engineering based on electro spun cerebral palsy. nanofibers Principal investigator C.-D. Peterlein Principal investigator(s) J.R. Paletta & S. Fuchs- Summary In this clinical study, the influence of Winkelmann repeated botulinum toxin injections on pain and Summary Previous studies showed that locomotion in childrens and adolescents with Nanoscaffolds represent suitable matrices for bone cerebral palsy is analysed (with special focus on the tissue engineering. The aim of the current upper extremity). investigations is to combine multi-jet electrospinning Funded by Merz Pharmaceuticals GmbH with electrospraying of MSC in order to achieve cell Funding period 2013 – 2016 seeded scaffolds. Environmental conditions within the process were optimized with respect to cell Title Clinical and radiological evaluation of cell free survival. By variations of the polymer used for collagen type I transplants nanofiber scaffold production, mechanic as well as Principal investigator(s) T. Efe osteoinductive properties should be enhanced. Summary A new cell-free collagen type I gel Funded by AO Foundation (CaReS®-1S, Arthro Kinetics, Krems/Donau, Austria) Funding period 2013 – 2015 has been introduced for the treatment of smaller local cartilage defects. Within an ex vivo model Title Expression of MMP-1, 3, 9, 13 and their different parameters of transplant stability were regulators NGAL and RECK in Chondrosarcoma" analyzed. Furthermore in a clinical study, long time Principal investigator(s) D. Malcherczyk & J. R. stability of the transplant is analyzed and Paletta demonstrates good clinical and radiological results. Summary Chondrosarcoma is the second most Funded by Arthro Kinetics, Krems/Donau, Austria common bone tumor in population older then 50 Funding period 2008 – 2015 years. Because of their heterogeneity, with differences in invasive and metastatic behavior, it is Title Multicenter Clinical Observation Using the important to identify biological markers fore Nanos femoral neck prosthesis accurate estimation of patient prognosis. In this Principal investigator(s) T. Efe project the influence of MMP-1, MMP-3, MMP-9 and Summary Prospective, multi center, observational MMP-13 as well as their regulators NGAL and RECK study focusing on effectiveness and safety of calcium on metastatic potential of chondrosarcoma is phosphate coated NANOS short stem prosthesis with investigated. respect to clinical and radiological long term (10 Funded by AXIS Foundation years) out come. Funding period 2014-2015 Funded by Smith & Nephew Funding period 2010 – 2021 Title Prospective, multicenter, randomized, double- blind, parallel-group, dose-response study of three
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Title Multicenter Clinical Observation Using the Title Biomechanical and kinematic evaluation after Cementless Version of the POLARSTEM unicompartmental and patellofemoral joint knee Principal investigator(s) T. Efe arthroplasty Summary The prospective randomized trial is part of Principal investigator(s) T.J. Heyse, B.J El-Zayat & S. a multicenter study focusing on the long term results Fuchs-Winkelmann of the cement less, hydroxyapatit coated version of Summary In vitro knee kinematics as well as loading the Polarstem. Clinical and radiological data were pressure in the lateral component were investigated collected 3 month, 1, 3, 5 and 10 years after before and after medial unicondylar knee implantation and analyzed with respect to Harris Hip arthroplasty (UKA). Subsequently influence of Scores, WOMAC and radiolucent lines according to additional pattelofemoral joint arthroplasty was Gruen evaluated. Funded by Smith & Nephew Funded by Smith & Nephew, Röhn-Klinikum Funding period 2010 – 2021 Funding period 2009 – 2015
Title Biomechanical evaluation after Title Analysis of different stem lengths and fixation unicompartmental knee arthroplasty techniques in hinged Total Knee Arthroplasty Principal investigator(s) T.J. Heyse, B.F. El Zayat & S. Principal investigator(s) Bilal Farouk El-Zayat & T.J. Fuchs-Winkelmann Heyse Summary In vitro knee kinematics was investigated Summary A numerical model, coupling rigid body before and after unicondylar knee arthroplasty kinematics and finite element analysis, was (UKA). It was shown that UKA kinematics is close to developed to evaluate and compare the effect of the native kinematics in different loading regimes. fixation technique and stem length in a hinged TKA Funded by Smith & Nephew Funded by Smith&Nephew Funding period 2009 – 2015 Funding period 2010 – 2015 Title Influence of lateral facetectomy on retropatellar contact pressure after knee TKA Title Biomechanical and kinematic evaluation after Principal investigator(s) B.F. El Zayat, T.J. Heyse & S. Mobile bearing unicompartmental knee arthroplasty Fuchs-Winkelmann Principal investigator(s) T.J. Heyse & S. Fuchs- Summary Within this study the kinematics and Winkelmann influence on retropatellar contact pressure after Summary In vitro knee kinematics as well as loading knee TKA through lateral patella facetectomy is pressure in the lateral component are investigated analyzed. before and after mobile bearing medial unicondylar Funded by Smith & Nephew knee arthroplasty (UKA). Data will compared with Funding period 2009 – 2015 those of fixed bearing UKA. Funded by Deutsche Knie-Gesellschaft, Biomet Title Kinematic investigations on the impact of Funding period 2014 – 2016 femoral component rotation in total knee arthroplasty Title Biomechanical and kinematic evaluation after Principal investigator(s) T.J. Heyse, B.F. El-Zayat & S. bicruciate retaining total knee arthroplasty Fuchs-Winkelmann Principal investigator(s) T.J. Heyse & S. Fuchs- Summary In vitro knee kinematics were investigated Winkelmann for natural knees and after implantation of normal as Summary In vitro knee kinematics as well as loading well as internally and externally malrotated femur pressures are investigated before and after a novel components in TKA. total knee arthroplasty (TKA), that preserves both Funded by Smith & Nephew cruciate ligaments. Funding period 2009 – 2015 Funded by Biomet Funding period 2014 – 2016 Title Influence of different inlay sizes on knee kinematics after unicompartmental knee Title Laser scanning retrieved TKA polyethylene arthroplasty inlays: Oxidized zirconium vs. conventional CoCr Principal investigator(s) T.J. Heyse, B.J El-Zayat & S. Principal investigator(s) T.J. Heyse Fuchs-Winkelmann Summary A retrieval analysis will be performed to Summary In vitro knee kinematics investigated a compare PE damage with femoral components from natural knee as well as after unicondylar knee the two different materials. arthroplasty (UKA). Evaluation of different inlay sizes Funded by Smith & Nephew (optimal, one size upgraded and one size Funding period 2014 – 2016 downgraded) on knee kinematics were observed. Funded by Smith & Nephew Funding period 2009 – 2015
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Contact Details: Baldingerstraße 35043 Marburg, General information about the institute Tel.:++49 (0) 6421-58 64914 Director: Professor Dr. Susanne Winkelmann
Research funding 99.746,22 €
Most important publications El-Zayat BF, Efe T, Heidrich A, Anetsmann R, Timmesfeld N, Fuchs-Winkelmann S, Schofer MD (2013) Objective assessment, repeatability, and agreement of shoulder ROM with a 3D gyroscope. BMC Musculoskelet Disord 14:72
Lakemeier S, Lind M, Schultz W, Fuchs-Winkelmann S, Timmesfeld N, Foelsch C, Peterlein CD (2013) A comparison of intraarticular lumbar facet joint steroid injections and lumbar facet joint radiofrequency denervation in the treatment of low back pain: a randomized, controlled, double-blind trial. Anesth Analg. 2013 Jul;117(1):228-35.
Heyse TJ, Figiel J, Hähnlein U, Schmitt J, Timmesfeld N, Fuchs-Winkelmann S, Efe T (2013) MRI after unicondylar knee arthroplasty: rotational alignment of components. Arch Orthop Trauma Surg 133(11):1579-86
Struewer J, Roessler PP, Schuettler KF, Ruppert V, Stein T, Timmesfeld N, Paletta JR, Efe T (2014) Influence of cyclical mechanical loading on osteogenic markers in an osteoblast-fibroblast co- culture in vitro: tendon-to-bone interface in anterior cruciate ligament reconstruction. Int Orthop 8(5):1083-9
Heyse TJ, El-Zayat BF, De Corte R, Scheys L, Chevalier Y, Fuchs-Winkelmann S, Labey L (2014) Biomechanics of medial unicondylar in combination with patellofemoral knee arthroplasty. Knee 21 Suppl 1:S3-9
Eberhardt O, Fernandez FF, Gabriel H, Wirth T, Fuchs-Winkelmann S, Peterlein CD (2014) Clubfoot associated with preaxial polydactyly. J Pediatr Orthop B 23(6):505-11
Heyse TJ, El-Zayat BF, De Corte R, Chevalier Y, Scheys L, Innocenti B, Fuchs-Winkelmann S, Labey L (2014) UKA closely preserves natural knee kinematics in vitro.Knee Surg Sports Traumatol Arthrosc. 2014 Aug;22(8):1902-10
Heyse TJ, Haas SB, Drinkwater D, Lyman S, Kim HJ, Kahn BA, Figgie MP (2014) Intraarticular fibrinogen does not reduce blood loss in TKA: a randomized clinical trial. Clin Orthop Relat Res 472(1):272-6
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Clinical Institutions
Department of Trauma-, Hand- and Reconstructive Surgery
Chair Professor S. Ruchholtz Funded by Kempkes Foundation Funding period until 2013 Main fields of research Research in the Department of Trauma- Hand- and Title Effects of induced hypothermia in a multiple Reconstructive Surgery is dedicated to preclinical trauma model in pig and clinical investigations in the fields of a) multiple Principal investigator(s) D. Eschbach, J. Mohr & M. injury, b) geriatric trauma and c) sports injuries. Frink Healing of tendons into bone (Schwarting, Summary Accidental hypothermia represents a Lechler, Frink et al.) leading cause of death in severely injured patients. Healing of osteoporotic fractures (Wack, Wirries, Therapeutic hypothermia, however, is commonly Aigner et al.) used after cardiac arrest. Therefore, the effects of Hypothermia (Eschbach, Frink et al.) therapeutic hypothermia following multiple trauma Biomechanics in fracture treatment (Frink, with severe lung injury, abdominal trauma, Bliemel, et al.) hemorrhagic shock and fracture in combination with induced hypothermia after cardiopulmonary Minimal-invasive spine surgery (Krüger, stabilization is evaluated in pigs over 48 hours in Oberkircher, et al.) order to proof survival. Minimal-invasive trauma surgery (Ruchholtz, Funded by Reinfried Pohl Foundation Zettl, Aigner et al.) Funding period since 2014 Geriatric fractures (Bücking, Eschbach, et al.)
TraumaNetwork DGU (Kühne, Ruchholtz, et al.) Title Biomechanics in fracture treatment Principal investigator(s) R. Zettl, C. Bliemel, Th. Research projects Müller & M. Frink Title Effects of bone morphogenetic protein 2 and 7 Summary The studies performed in this research (BMP-2; BMP-7) onto the process of tendon-bone- project deal with the effect of valgisation in proximal integration in a vitro Co-Culture model femur fractures, the biomechanical testing of two Principal investigator(s) T. Schwarting, P. Lechler & established osteosyntheses (nailing vs. plating and M. Frink cement augmented vs. non-cement augmented) in a Summary Graft incorporation and ligamentization human cadaver model and with the question if plate are high critical factors in anterior cruciate ligament fixation in acetabular fractures need screw fixation surgery, related to the biological processes at in the symphysis or if supraacetabular fixation and tendon-bone interface. Aim of the present project is support is sufficient. to investigate the influence of growth factors like Funded by Fa. Zimmer bone morphogenetic protein (BMP-2; BMP-7) on Funding period 2014 murine osteoblasts and fibroblasts within an in vitro co-culture model and its influence onto the tendon- Title Minimal-invasive spine surgery bone-healing. Furthermore, the influence of COX-1 Principal investigator(s) A. Krüger, L. Oberkircher, and-2 inhibition was elucidated. M. Bergmann, F. Floßdorf & C. Dorschel Funded by Intramural funding Summary The treatment of osteoporotic vertebral Funding period since 2013 fractures by cement augmenting procedures is well accepted in spine surgery. Different procedures and Title Effects of local application of osteoanabolic their biomechanical performance are evaluated. A substances in osteoporotic fracture healing fracture model has been standardized and the first Principal investigator(s) C. Wack, A. Wirries & R. biomechanical tests have been performed. In Aigner addition, a survey among german surgeons Summary This project studies the effects of regarding the use of cement augmentation established as well as promising new osteoanabolic procedures in spine surgery was conducted and substances on bone fracture healing in vivo. published. Experiments are carried out in a rat-fracture model comparing normal to osteoporotic (ovariectomized) Title Minimal invasive trauma surgery: fracture rats applying substances locally in the fracture or stabilization in geriatric trauma patients systemically by subcutaneous injection and Principal investigator(s) S. Ruchholtz, R. Zettl, B. comparing healing results through radiological, Bücking, C. Bliemel & J. Mohr biomechanical and histological findings.
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Summary Along with the increase of the aging Frühe geriatrische Mitbehandlung in der society higher rates of complex osteoporotic Alterstraumatologie. Eine systematische fractures of the humerus, the pelvic ring, the Literaturanalyse. Dtsch Arztebl Int 110(15):255-62 acetabulum and in peri-prosthetic or peri-implant situations are seen. Our study group follows new Eschbach DA, Oberkircher L, Bliemel C, Mohr J, techniques of minimal invasive stabilization of these Ruchholtz S, Buecking B (2013) Increased age is not complicated fractures within prospective clinical associated with higher incidence of complications, studies. longer stay in acute care hospital and in hospital mortality in geriatric hip fracture patients. Maturitas Title Geriatric fractures 74(2):185-9. Principal investigator(s) C. Bliemel, B. Bücking, S. Ruchholtz, D. Eschbach & J. Mohr Buecking B, Struewer J, Waldermann A, Horstmann Summary We investigate the role of the K, Schubert N, Balzer-Geldsetzer M, Dodel R, Bohl K, rehabilitation after hip fracture with a prospective Ruchholtz S, Bliemel C (2014) What determines observational study. In addition, we evaluate fixation health-related quality of life in hip fracture patients of trochanteric fractures with a new anatomical at the end of acute care? - a prospective shaped proximal femoral nail and compare the observational study. Osteoporos Int 25(2):475-84 effects of Teriparatide with those of Risedronate on lumbar spine bone mineral density in osteoporotic Buecking B, Eschbach D, Bliemel C, Oberkircher L, patients with low bone mass and a recent Struewer J, Ruchholtz S, Sachs UJ (2014) pertrochanteric hip fracture. Effectiveness of vitamin K in anticoagulation reversal Funded by Fa. Zimmer, Fa. Lilly for hip fracture surgery - A prospective observational Funding period 2010 – 2013 study. Thromb Res 133(1):42-7
Title TraumaNetwork DGU Schüttler KF, Strüwer J, Roessler PP, Gesslein M, Principal investigator(s) C. Kühne, S. Rucholtz, F. Rominger MB, Ziring E, Efe T (2014) Patellofemoral Debus & C. Mand osteoarthritis after Insall's proximal realignment for Summary In order to guarantee an optimum of recurrent patellar dislocation. Knee Surg Sports nationwide severe trauma care in 2006 the Traumatol Arthrosc 22(11):2623-8 TraumaNetwork DGU® - project of the German Society of Trauma Surgery (Deutsche Gesellschaft für Buecking B, Mohr J, Bockmann B, Zettl R, Ruchholtz Unfallchirurgie - DGU) was initiated. The working S (2014) Deltoid-split or Deltopectoral Approaches group in our department analyses the impact of this for the Treatment of Displaced Proximal Humeral project on the quality of trauma care in our country. Fractures? Clin Orthop Relat Res 472(5):1576-85 Funded by DGU (German Society of Trauma Surgery); GDV (Gesamtverband Deutscher Versicherer) Contact Details: Funding period 2011 – 2013 Baldingerstrasse 35043 Marburg, Phone:++49 (0) 6421-58 66216 Director: Professor Dr. Steffen Ruchholtz
General information about the institute
Research funding 190.569,02 €
Most important publications Mand C, Müller T, Lefering R, Ruchholtz S, Kühne CA (2013) A Comparison of the Treatment of Severe Injuries Between the Former East and West German States- Vergleich der Schwerverletztenversorgung in den neuen und alten deutschen Bundesländern. Dtsch Arztebl Int 110(12):203-10
Buecking B, Timmesfeld N, Riem S, Bliemel C, Hartwig E, Friess T, Liener U, Ruchholtz S, Eschbach D (2013) Early Orthogeriatric Treatment of Trauma in the Elderly: A Systematic Review and Metaanalysis-
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Department of Urology and Pediatric Urology Prostate Cancer Centre
Chair Professor R. Hofmann sum, sPGE2 was increased in patients with OAB and decreased after BoNT-A treatment. Thus, sPGE2 may Main fields of research serve as biomarker in diagnostic and therapy Oncology monitoring [3]. Addressing possible actions of BCG immunotherapy Funded by Ipsen Pharma in bladder cancer, the functions of TLR-4/9 were investigated as possible targets in bladder cancer cells [1]. A related project focussed on the responses General information about the institute of the cells towards inhibition of receptor tyrosine kinases that can be aberrantly activated in bladder Research funding 58.996,60 € cancer. An ongoing project deals with RNA biomarkers in prostate cancer.
Overactive bladder syndrome (OAB) Most important publications The role of prostaglandin E2 (PGE2) in patients with Hänze J, Henrici M, Hegele A, Hofmann R, Olbert, PJ idiopathic overactive bladder syndrome was (2013) Epithelial mesenchymal transition status is investigated supporting its possible value to objectify associated with anti-cancer responses towards clinical diagnosis and responsiveness towards receptor tyrosine-kinase inhibition by dovitinib in botulinum toxin A (BoNT-A) therapy [2]. human bladder cancer cells. BMC Cancer 13, 589
Kidney injury Hegele A, Knippschild S, Frohme C, Hänze J, Olbert An experimental study identified TLR-3 as critical P, Hofmann R (2014) Changes in prostaglandin E2 in component for the pathomechanism of acute kidney patients with idiopathic overactive bladder injury following ischemia and reperfusion (IR) [3]. In syndrome after botulinum toxin type A treatment: is a clinical study, certain profiles of NGAL and KIM-1 in there a clinical benefit? BMC Urol 14, 85 serum and urine were recognized as promising valuable markers for postrenal kidney injury [4]. Urbschat A, Gauer S, Paulus P, Reissig M, Weipert C, Ramos-Lopez E, Hofmann R, Hadji P, Geiger H, Obermuller N (2014) Serum and urinary NGAL but Research projects not KIM-1 raises in human postrenal AKI. Eur J Clin Title Effects of TKI258 on bladder cancer cell lines Invest 44, 652-659 with different EMT pattern Principal investigator J. Hänze & P. Olbert Paulus P, Rupprecht K, Baer P, Obermuller N, Summary Aberrant cellular processes in bladder Penzkofer D, Reissig C, Scheller B, Holfeld J, cancer comprise altered signaling of receptor Zacharowski K, Dimmeler S, Schlammes J, Urbschat, tyrosine kinases. Here we demonstrated that the A. (2014) The early activation of toll-like receptor cellular epithelial-mesenchymal transition status is (TLR)-3 initiates kidney injury after ischemia and associated with responses towards tyrosine kinase reperfusion. PLoS One 9, e94366 inhibition by dovitinib (Novartis). Dovitinib was more Frohme, C., Ludt, F., Varga, Z., Olbert, P. J., effective in epithelial-like than in mesenchymal-like Hofmann, R., and Hegele, A. (2014) TOT approach in bladder cancer cells. Therefore, determination of the stress urinary incontinence (SUI) - outcome in obese EMT status may offer to predict treatment response female. BMC Urol 14, 20 [2]. Funded by Novartis Institutes for Biomedical Hegele A, Goebell P, Matz U, Neuhaus T (2014) Research Monotherapy with intravenous vinflunine in patients with advanced or metastatic urothelial cancer after Title Evaluation of PGE2 in overactive bladder failure of a platinum-containing regimen: a syndrome (OAB) retrospective analysis of German routine data. Urol Principal investigator(s) A. Hegele Int 92, 174-179 Summary PGE2 has been noticed as critical mediator being involved in OAB. Here, we analyzed serum PGE2 levels in OAB patients receiving intravesical Contact Details: BoNT–A administration representing a safe and Baldingerstraße 35043 Marburg, effective therapy for refractory idiopathic OAB. In Tel.:++49 (0) 6421-58 66239 Director: Professor Dr. Rainer Hofmann
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Department of Visceral-, Thoracic and Vascular Surgery
Chair Professor D. Bartsch Title Clinical and genetic evaluation of familial pancreatic cancer Principal investigator(s) D. Bartsch, E. P. Slater & V. Main fields of research Fendrich AG Bartsch: familial pancreatic cancer, Summary Familial pancreatic cancer (FPC) is defined neuroendocrine tumors of the GI –tract by families with at least two first- degree relatives with confirmed pancreatic ductal adenocarcinoma Our department has a broad spectrum of all kind of (PDAC). We want to explore a screening program surgical, molecular and genetic research. In our main with a multidisciplinary approach under research focus is to understand the development and protocol conditions. Further research will done in progression of pancreatic tumor. A sort of tumor establish new biomarkers for screening of individuals which had still a bad prognosis instead of all research at risk. A national database will build up. and clinical efforts. Also we want to become more Funded by Deutsche Krebshilfe informations about the relative rare forms of familial Funding period 2013 – 2016 pancreatic cancer. Together with the Deutsche Krebshilfe we work on a national database on this Title INTRANS Study topic. Further we want to establish and develop Principle investigators K. Manschuw & D. K. Bartsch modern surgical procedures for robotic –assisted Summary Surgical site infections are the third most operations of the goiter, pancreas. In thoracic frequent type of nosocomial infections. Literature surgery we evaluate the use of new laser systems in data for skin closure in elective abdominal surgery lung metastases surgery. are still deficient. This project is designed as a prospective randomized controlled single center Research projects study in order to define the gold standard for wound closure in elective abdominal surgery Title Molecular mechanisms in the development of (intracutaneous suture vs. transcutaneous skin pancreatic cancer stapling). Principal investigator(s) Trilateral project, together Funded by UKGM – University Medical Centre with Dr. Areej Alkahtib, Bethlehem University and Giessen and Marburg Dr. Yuval Dor, The Hebrew University of Jerusalem Funding period 2013 – 2016 Summary Pancreatic cancer has a poor long term survival. This trilateral project wants to evaluate the Title Chemoprevention with Enalapril, ASS and a origin cell for this disease. So by analysis of the cell Somatostatinanaloga in MEN 1 knockout mice methylation patterns, the researchers are able to Principle investigator (s) C. Lopez distinguish the different cell types. An additional Summary To evaluate the longterm outcome of a project should concentrate on molecular medical treatment with enalapril or ASS or a mechanisms in the development of pancreatic somatostatinanaloga in an MEN 1 Knockout mouse cancer, like for example the dysfunction of the gene modell. BRCA2. Funded by Anneliese Pohl Foundation Funded by DFG – German Research Foundation Funding period 2013 – 2016 Funding period 2014 – 2016
Title The role of SNAIL as a key protein in epithelial Title Role of Rac1b and MMP-3 for the development to mesenchymal transition (EMT) in pancreatitis in a and progression of pancreatic cancer transgene mouse model Principal investigator(s) J. Waldmann Principal investigator(s) M. Albers Summary Matrix metalloproteinases (MMP) are Summary SNAIL is a kex protein in EMT. Aim of the known as key drivers of tumor progression that study is to evaluate the role of SNAIL in the course of originate primarily from stromal cells activated by pancreatitis in terms of sererity of inflammation, the developing tumor. In pancreatic cancer it was necrosis and regeneration in a mouse model of found that MMP – 3 was expressed together with genetically abrogation and chemical inhibition of Rac1b. In this study we want to know what is the SNAIL. Pancreatitis is provoked by intraperitoneal role of both MMP-3 and Rac1b for the development application of cerulean. and maybe the progression of pancreatic cancer. Funded by Cooperation between Hessen and Rhön Funded by Deutsche Krebshilfe Klinikum Funding period 2013 – 2015 Funding period 2013 – 2015
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Title Marburg surgical curriculum Bartsch DK, Slater EP, Albers M, Knoop R, Chaloupka Principle investigator A. Damanakis B, Lopez CL, Fendrich V, Kann PH, Waldmann J Summary The Marburg surgical curriculum (2014) Higher risk of aggressive pancreatic (Marburger chirurgisches Weiterbildungscurriculum neuroendocrine tumors in MEN1 patients with MCW) wants to improve residents training. With a MEN1 mutations affecting the CHES1 interacting focus on the first 2 years of residency (common MENIN domain. J Clin Endocrinol Metab trunk) it offers high quality courses by experienced 99(11):E2387-91 clinicians of various disciplines. Topics covered are perioperative management of a surgical patient Di Dalmazi G, Kisker C, Calebiro D, Mannelli M, Canu (perioperative management of coagulation, sepsis, L, Arnaldi G, Quinkler M,Rayes N, Tabarin A, Laure standard antibiotic therapy etc.) and surgical basic Jullié M, Mantero F, Rubin B, Waldmann J, Bartsch skills (knot tying, suturing, laparoscopy basics, DK, Pasquali R, Lohse M, Allolio B, Fassnacht M, operation techniques for starters). The duration of Beuschlein F, Reincke M (2014) Novel somatic the course is two years and apart from residents mutations in the catalytic subunit of the protein currently undergoing training at the Marburg kinase A as a cause of adrenal Cushing's syndrome: a University hospital, residents from associated European multicentric study. J Clin Endocrinol Metab hospitals are invited to take part. 99(10):E2093-100 Funded by Mittelhessische Medizin Stiftung, Behandlungsexzellenz und Netzwerkmedizin of the Knoop RF, Sparn M, Waldmann J, Plassmeier L, Rhön Klinikum AG Bartsch DK, Lauth M, Hudemann C, Fendrich V Funding period 2013 – 2015 (2014) Chronic pancreatitis and systemic inflammatory response syndrome prevent impact of chemotherapy with gemcitabine in a genetically engineered mouse model of pancreatic cancer. General information about the institute Neoplasia 16(6):463-70
Research funding 451.825,78 € Assié G, Letouzé E, Fassnacht M, Jouinot A, Luscap W, Barreau O, Omeiri H, Rodriguez S, Perlemoine K, René-Corail F, Elarouci N, Sbiera S, Kroiss M, Allolio B, Waldmann J, Quinkler M, Mannelli M, Mantero F, Most important publications Papathomas T, De Krijger R,Tabarin A, Kerlan V, Bartsch DK, Albers M, Knoop R, Kann PH, Fendrich Baudin E, Tissier F, Dousset B, Groussin L, Amar L, V, Waldmann J (2013) Enucleation and limited Clauser E, Bertagna X, Ragazzon B, Beuschlein F, Libé pancreatic resection provide long-term cure for R, de Reyniès A, Bertherat J (2014) Integrated insulinoma in multiple endocrine neoplasia type 1. genomic characterization of adrenocortical Neuroendocrinology 98(4):290-8 carcinoma. Nat Genet 46(6):607-12
López CL, Langer P, Waldmann J, Fendrich V, Sitter H, Nies C, Bartsch DK (2013) Shortness: an unknown Contact Details: phenotype of multiple endocrine neoplasia type 1. Baldingerstraße, 35043 Marburg, Eur J Endocrinol 169(1):133-7 Tel.:++49 (0) 6421-586 6441 Director: Professor Dr. Detlef Bartsch Heeger K, Fendrich V, Waldmann J, Langer P, Kanngießer V, Bartsch DK (2013) Reduced complication rate after modified binding purse- string-mattress sutures pancreatogastrostomy versus duct-to-mucosa pancreaticojejunostomy. Surgeon 11(5):246-52
Lopez CL, Falconi M, Waldmann J, Boninsegna L, Fendrich V, Goretzki PK, Langer P, Kann PH, Partelli S, Bartsch DK (2013) Partial pancreatico- duodenectomy can provide cure for duodenal gastrinoma associated with multiple endocrine neoplasia type 1. Ann Surg 257(2):308-14
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Department of Gynaecology, Gynaecological Endocrinology and Oncology
Chair Professor U. Wagner either stopping overtreatment or withheld of optimal surgical care. Endpoints include overall Main fields of research survival, quality of life and tolerability. The main focus of research is placed on basic and Funded by DLR, BMBF – Federal Ministry of clinical research in gynaecologic oncology, ovarian Education and Research and breast cancer, cancer therapy related Funding period 2008 – 2017 osteoporosis. Basic research comprises the evaluation of immunological regulation in cancer Title Stealth liposomal doxorubicin versus development and progression. In Obstetrics research carboplatin/paclitaxel in patients with ovarian is focussed on preeclampsia and the development of cancer recurrence between six and twelve months new methods in prenatal diagnosis. after previous platinum based chemotherapy (MITO- 8) Research projects Principal investigator(s) Dr. Sandro Pignata (Italy), U. Wagner & K. H. Baumann Title Transcriptional Signal pathways for the Summary Ovarian cancer is the second most polarization of tumor-associated Macrophages in frequent gynaecological neoplasm but it is the first in Ovarian Cancer order of mortality. Following initial surgical and Principal investigator(s) U. Wagner & R. Müller systemic therapy, 70% of patients with ovarian Summary Tumor-associated macrophages (TAM) cancer in an advanced stage and 25% of patients seem to have a strong impact on the development with early stage (FIGO I and II) will have disease and progress of cancer. We demonstrated that progression or recurrence and require a second line ovarian cancer patients could be divided into two chemotherapy. In patients with progression subgroups based on the TAM phenotype in ascites. orrecurrence more than 12 months after completion In the present study, the project focusses on the of first-line therapy, reinduction with carboplatin/ evaluation of the transcriptional signal pathways in paclitaxel is regarded as standard treatment. But in the tumor associated macrophages from human patients with progression or recurrence between 6 ovarian carcinomas. Main focus lies on the and 12 months, the evidence is not as clear-cut. It transcription factors IL-1ß and IL-6 and the genome has been hypothesized that these patients might wide sequencing of the chromatin binding benefit from an artificial prolongation of the areas in contrast to normal macrophages. platinum-free interval through the use of anon- Funded by Anneliese Pohl Foundation platinum agent. The proposed prospectively Funding period 2014 – 2015 randomized and controlled multicenter phase III trial
MITO-8 will test the hypothesis whether the Title Lymphadenectomy In Ovarian Neplasms – LION treatment sequence ‘stealth liposomal doxorubicin Principal investigator(s) U. Wagner, Prof. Dr. A. du followed on further progression by Bois and Dr. P. Harter (Kliniken Essen-Mitte (KEM), carboplatin/paclitaxel’ is superior to the reverse Evang. Huyssens-Stiftung/Knappschaft GmbH, Klinik sequence in patients with ovarian cancer recurrence für Gynäkologische Onkologie between 6 and 12 months after previous platinum Summary Pelvic and para-aortic lymphadenectomy based chemotherapy. The study will evaluate overall (LNE) is well established as surgical staging in early survival but will also focus on quality of life and stage ovarian cancer. The role of LNE in advanced tolerability. The Arbeitsgemeinschaft Gynäkologische ovarian cancer is unclear. Retrospective analyses Onkologie (AGO) Study Group will take part in MITO- indicate a potential benefit of LNE in patients with 8 within the framework of the Gynecologic Cancer macroscopically complete intraabdominally Intergroup (GCIG), an international network of resection. However, prospective randomized trials gynaecologic oncology study groups. are lacking. The lack of sound evidence in this area is Funded by DLR, BMBF – Federal Ministry of reflected by the heterogeneous LNE usage in Education and Research Germany. This prospectively randomized controlled Funding period 2010 – 2016 multicentre phase III trial will clarify the role of LNE in advanced ovarian cancer, thereby either establish Title Function and therapeutic potential of PPARβ/δ LNE as evidence-based part of ovarian cancer in tumor-associated macrophages in human ovarian surgery in routine care or disregard its use. Both cancer results would provide benefit for the patient by
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Clinical Institutions
Principal investigator(s) S. Müller-Brüsselbach & S. bevacizumab in patients with platinum-sensitive Reinartz recurrent ovarian cancer. An ENGOT/GCIG Trial. Summary Tumor-associated macrophages (TAM) Principal investigator(s) I. Pfisterer (International seem to have a strong impact on the development Coordinator & K. Baumann (PI Germany) and progress of cancer. We demonstrated that Summary Patients with first recurrence of epithelial ovarian cancer patients could be divided into two ovarian cancer (EOC), fallopian tube carcinoma (FTC) subgroups based on the TAM phenotype in ascites. or primary peritonealcarcinoma (PPC) and sensitive In the present study, the clinical relevance of TAM to platinum-based treatment regardless of FIGO subtypes and the role of ligand-regulated stage, histological grades and types. So far, transcription factor PPARß/ in functional TAM carboplatin/pegylated liposomal doxorubicin was polarization should be investigated. one of the options with the best therapeutic index Funded by Wilhelm-Sander Foundation for patients with platinum-sensitive recurrence and Funding period 2011 – 2016 carboplatin/gemcitabine/bevacizumab has shown a dramatic improvement in PFS, the rationale of this Title Regulation of glucose metabolism by PPARβ/δ clinical trial is to evaluate the best platinum-based ligands in ovarian carcinoma: Mechanism and regimen in combination with bevacizumab in therapeutic potential platinum-sensitive recurrence. The question would Principal investigator(s) V. Rohnalter, S. Müller- be answered whether the addition of bevacizumab Brüsselbach & S. Reinartz to pegylated liposomal doxorubin (cin/carboplatin is Summary The PPARβ/δ target gene PDK4 superior to bevacizumab combined with (Pyruvatdehydrogenase-Kinase 4) is overexpressed gemcitabine/carboplatin. TRIAL DESIGN of this in tumor-associated macrophages (TAM) and tumor- academic trial: Prospective, open-label, initiating cells (TIC) in ascites of ovarian cancer multinational, randomized, two arm, superiority patients. PDK4 plays a central role in glucose Phase III trial. 654 patients will be enrolled (327 per metabolism and favours glycolysis which is essential arm). Primary objective: The primary efficacy for the survival of TICs under hypoxia. In this study, outcome measure for this clinical trial is investigator- we test the hypothesis if inverse PPARβ/δ-agonists determined progression-free survival (PFS). can block induction of glycolysis by PDK4, thereby Recruitment: N=654 patients will be recruited into influencing survival / stem cell properties of TIC as this clinical trial over a period of 30 months. Primary well as protumorigenic functions of TAM. analysis will be done after 564 PFS events achieved. Funded by UKGM – University Hospital Giessen and The analysis with respect to OS will be done after the Marburg last patient randomized has completed the 30 Funding period 2014 – 2015 month follow-up (corresponds to 60 months after the randomization of the first patient). Title Differential chromatin signatures and Funded by AGO Research GmbH (an academic expression pattern of tumor-associated research group), Wiesbaden macrophages in ovarian cancer Funding period 2012 – 2017 Principal investigator(s) T. Adhikary & S. Reinartz Summary Tumor-associated macrophages (TAM) Title S3-Guideline on Diagnostics, Therapy and play a pivotal role in tumor development and Follow-up of Malignant Ovarian Tumours progession, but little is known about regulation of Principal investigator(s) U. Wagner TAM polarization. In this study we focus on Summary The guideline was compiled with the aim epigenetic markers essential for stability and of providing high-risk groups with advice on reversibility of TAM polarization in ovarian cancer. diagnostics, surgical and systemic therapy in early Ovarian cancer is often associated with malignant and advanced stages of disease in ovarian cancer. A ascites which contains large amounts of TAM lot of emphasis has been placed on follow-up care, sufficient for genome-wide sequencing and rehabilitation, palliative therapy andpsycho- expression analysis. Correlation of epigenetic oncological counselling. The recommendations are markers with clinical data should provide new for physicians working both in hospitals and insights in clinically relevant mechanisms in TAM. outpatient clinics, nursing staff and other medical Funded by UKGM – University Hospital Giessen and partners involved in treating patients with malignant Marburg ovarian tumours. As it also covers the topics Funding period 2013 – 2014 'Screening' and 'Follow-up', registered physicians working in their own practice are also an important Title A prospective randomized Phase III trial of target audience of this guideline. It is additionally carboplatin / gemcitabine/bevacizumab vs. intended to offer guidance to affected patients and carboplatin /pegylated liposomal doxorubicin persons seeking more information aswell as providing a basis for the gynaecological cancer centres currently being set up in Germany.
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Funded by Deutsche Krebshilfe Reinartz S, Schumann T, Finkernagel F, Wortmann A, Funding period 2012 – 2014 Jansen JM, Meissner W, Krause M, Schwörer AM, Wagner U, Müller-Brüsselbach S, Müller R (2014) Title Angiogenic factors in early –versus late onset Mixed-polarization phenotype of ascites-associated preeclampsia(PE) and HELLP-Syndrome macrophages in human ovarian carcinoma: Principal investigator(s) M. Kühnert correlation of CD163 expression, cytokine levels and Summary Prognosis of patients with symptoms of early relapse. Int J Cancer 134(1):32-42 preeclampsia and HELLP-Syndrome. Correlation of Trillsch F, Mahner S, Woelber L, Vettorazzi E, Reuss worsening clinical course with early and late onset. A, Ewald-Riegler N, de Gregorio N, Fotopoulou C, PE with changes in the angiogenic profile and Schmalfeldt B, Burges A, Hilpert F, Fehm T, Meier W, implications in identification of the women for Hillemanns P, Hanker L, Hasenburg A, Strauss HG, appropriate patient management and possible Hellriegel M, Wimberger P, Baumann K, Keyver-Paik future therapies on the reduction of s Ftt-1 levels. MD, Canzler U, Wollschlaeger K, Forner D, Pfisterer J,
Schroeder W, Muenstedt K, Richter B, Kommoss F, Title Prognostic value of quantitative fibronectin in Hauptmann S, du Bois A (2014) Age-dependent Preterm Birth differences in borderline ovarian tumours (BOT) Principal investigator(s) M. Kühnert regarding clinical characteristics and outcome: Summary Eurofibronectin Study: Prognostic value of results from a sub-analysis of the Arbeitsge- quantitative fibronectin, cervical length and vaginal meinschaft Gynaekologische Onkologie (AGO) exam in women with preterm contractions. ROBOT study. Ann Oncol 25(7):1320-7 Funded by Hologic (test will be reimbursed) Funding period 2013 – 2014 Hadji P, Jackisch C, Bolten W, Blettner M, Hindenburg HJ, Klein P, König K, Kreienberg R, Rief Title EPICE-Study W, Wallwiener D, Zaun S, Harbeck N (2014) Principal investigator(s) S. Schmidt (retired) & R. F. COMPliance and Arthralgia in Clinical Therapy: the Maier COMPACT trial, assessing the incidence of arthralgia, Summary Health service research in obstetrics and compliance within the first year of adjuvant concerning mode of delivery of preterm birth (until anastrozole therapy. Ann Oncol 25(2):372-7 12/2015). Kann PH, Münzel M, Hadji P, Daniel H, Flache S, Funded by EU Nyarango P, Wilhelm A (2014) Alterations of Cortisol Funding period 2011 – 2015 Homeostasis May Link Changes of the Sociocultural
Environment to an Increased Diabetes and Metabolic Risk in Developing Countries: A Prospective Diagnostic Study Performed in General information about the institute Cooperation With the Ovahimba People of the Kunene Region/Northwestern Namibia. J Clin Research funding 1.189.500,73 € Endocrinol Metab 2014 Dec 18:jc20142625. [Epub ahead of print].
Würstlein R, Degenhardt F, Duda V, Madjar H, Merz Most important publications E, Mundinger A, Ohlinger R, Peisker U, Schulz- Adhikary T, Brandt DT, Kaddatz K, Stockert J, Naruhn Wendtland R, Warm M, Hahn M (2014) [Evaluation S, Meissner W, Finkernagel F, Obert J, Lieber S, of the nationwide DEGUM breast ultrasound training Scharfe M, Jarek M, Toth PM, Scheer F, Diederich program]. Ultraschall Med 35(4):345-9 WE, Reinartz S, Grosse R, Müller-Brüsselbach S, Müller R (2013) Inverse PPARβ/δ agonists suppress Axt-Fliedner R, Tenzer A, Kawecki A, Degenhardt J, oncogenic signaling to the ANGPTL4 gene and inhibit Schranz D, Valeske K, Vogel M, Kohl T, Enzensberger cancer cell invasion. Oncogene 32(44):5241-52 C (2014) Prenatal assessment of ventriculocoronary connections and ventricular endocardial fibro- du Bois A, Floquet A, Kim JW, Rau J, del Campo JM, elastosis in hypoplastic left heart. Ultraschall Med Friedlander M, Pignata S, Fujiwara K, Vergote I, 35(4):357-63 Colombo N, Mirza MR, Monk BJ, Kimmig R, Ray- Coquard I, Zang R, Diaz-Padilla I, Baumann KH, Mouret-Reynier MA, Kim JH, Kurzeder C, Lesoin A, Contact Details: Vasey P, Marth C, Canzler U, Scambia G, Shimada M, Baldingerstraße 35043 Marburg, Calvert P, Pujade-Lauraine E, Kim BG, Herzog TJ, Phone:++49 (0) 6421-58 66210 Mitrica I, Schade-Brittinger C, Wang Q, Crescenzo R, Director: Professor Dr. Uwe Wagner Harter P (2014) Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol 32(30):3374-82
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Clinical Institutions
Children’s Hospital
Chair Professor R. F. Maier Summary Blinded randomized multicenter trial to compare the effect of restrictive versus liberal red Prof. Dr. M. Zemlin – “Allergy and blood cell transfusion thresholds on long-term Developmental Immunology” neurodevelopmental outcome in extremely low birth Prof. Dr. R. F. Maier – “Neonatology and weight infants. Funded by DFG – German Science Foundation Neuroprotection” Funding period 2011 – 2015 Dr. A. Renigunta – “Pediatric Nephrology” Title Sauerstoff-abhängige Schädigung des unreifen Main fields of research Gehirns und der unreifen Retina und die The research areas of the Children´s Hospital Schutzwirkung von Erythropoietin Marburg are allergy, developmental immunology, Principal investigator(s) R. F. Maier (Marburg) & B. neonatology, neuroprotection, and pediatric Lorenz (Giessen) nephrology. We pursue clinical research as well as Summary The aim of this animal study is to basic research based on a broad spectrum of investigate the effect of hypoxia and hyperoxia on techniques such as molecular biology, the immature brain and retina as well as the electrophysiology, cellular biology, mass neuroprotective effects of erythropietin. spectrometry and others. Our research projects are Funded by von Behring-Röntgen Foundation funded by the European Union, the German Funding period 2011 – 2013 Research Council (DFG), the State Hessen, the von- Behring-Röntgen-Stiftung, and several other Title Prevention of chronic lung disease in very low institutions. birth weight neonates by inhaled NO (INOT-27- Studie) Research projects Principal investigator(s) R. F. Maier & M. Zemlin Title Effective Perinatal Intensive Care in Europe - Summary In this European multicenter randomized Translating knowledge into evidence-based practice controlled clinical trial, the efficacy and safety of (EPICE) inhaled NO to prevent chronic lung disease in very Principal investigator(s) R. F. Maier, Germany low birth weight infants is studied. (Steering Committee) Funded by Industry Summary The EPICE project uses quantitative and Funding period 2006 –2015 qualitative approaches to build a knowledge base about the adoption of evidence-based medical interventions for the care of very preterm babies in 18 regions from 12 European countries. General information about the institute Funded by EU – European Union
Funding period 2011 - 2015 Research funding 715.389,87 €
Title Characterization of plasma cell subsets in allergic bronchial asthma Principal investigator(s) M. Zemlin Most important publications Summary This project is part of the Transregio/SFB Gabler J, Wittmann J, Porstner M, Renz H, Jäck HM, 22 “Allergic diseases of the lung” and aims to better Abram M, Zemlin M (2013) Contribution of understand the factors that lead to the migration, microRNA 24-3p and Erk1/2 to interleukin-6- differentiation and survival of plasma blasts and mediated plasma cell survival. Eur J Immunol plasma cells to produce IgE antibodies against 43(11):3028-37 allergens. Funded by DFG – German Research Council Wagner JJ, Bedarf JR, Russ M, Grosch-Ott S, Keckel T, Funding period 2009 –2014 Hiebl B, Schell H, Unger JK (2013) Adverse Influence of Mixed Acidemia on the Biocompatibility of Title Effects of transfusion thresholds on Continuous Veno-Venous Hemofiltration With neurocognitive outcome of extremely low birth Respect to the Lungs. Artif Organs 37(12):1049-58 weight infants (ETTNO) Principal investigator(s) R. F. Maier (Steering Dorn F, Wirth L, Gorbey S, Wege M, Zemlin M, Committee) & M. Zemlin Maier RF, Lemmer B (2014) Influence of acoustic
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Clinical Institutions stimulation on the circadian and ultradian rhythm of premature infants. Chronobiol Int 31(9):1062-74
Leonhardt C, Margraf-Stiksrud J, Badners L, Szerencsi A, Maier RF (2014) Does the 'Teddy Bear Hospital' enhance preschool children's knowledge? A pilot study with a pre/post-case control design in Germany. J Health Psychol 19(10):1250-60
Rogosch T, Herrmann N, Maier RF, Domann E, Hattesohl A, Koczulla AR, Zemlin M (2014) Detection of bloodstream infections and prediction of bronchopulmonary dysplasia in preterm neonates with an electronic nose. J Pediatr 165(3):622-4
Rogosch T, Kerzel S, Dey F, Wagner JJ, Zhang Z, Maier RF, Zemlin M(2014) IgG4 and IgE Transcripts in Childhood Allergic Asthma Reflect Divergent Antigen-Driven Selection. J Immunol 193(12):5801-8
Watzer B, Lusthof KJ, Schweer H (2014) Abortion after deliberate Arthrotec® addition to food. Mass spectrometric detection of diclofenac, misoprostol acid, and their urinary metabolites. Int J Legal Med 2014 Dec 19
Peters DM, Vadász I, Wujak L, Wygrecka M, Olschewski A, Becker C, Herold S, Papp R, Mayer K, Rummel S, Brandes RP, Günther A, Waldegger S, Eickelberg O, Seeger W, Morty RE (2014) TGF-β directs trafficking of the epithelial sodium channel ENaC which has implications for ion and fluid transport in acute lung injury. Proc Natl Acad Sci USA 111(3):E374-83
Contact Details: Baldingerstraße 35043 Marburg, Tel.:++49 (0) 6421-58 66229 Director: Professor Dr. Rolf F. Maier
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Department of Otolaryngology, Head & Neck Surgery
Chair Professor J. A. Werner hearing loss (SSHL). Patients presenting with unilateral SSHL within 7 days after onset and Main fields of research meeting all in- and exclusion criteria will be Our research is mainly focusing on aspects relating randomized into 2 cohorts in a ratio of 2:1 between to the progress and the development of head and active treatment and placebo. Study treatment and neck cancer as well as on pathomechanisms all study assessments will be performed in an underlying the development of vascular anomalies in outpatient setting at designated clinical study sites. the head and neck area. The goal of the OBJECTIVES/AIM OF THE STUDY: The aim of this investigations is to better understand the biology of study is to evaluate the efficacy of Ancrod treatment these important diseases and to identify and develop on hearing ability in patients suffering from SSHL. new therapeutic approaches that can be used in Funded by Nordmark GmbH their treatment. Funding period 2013 – 2015
Research projects Title Immunohistochemical differentiation of Title Investigations regarding a possible association vascular anomalies of the head and neck – with of vascular anomalies with human papilloma virus emphasis on GLUT-1, D2-40 and WT-1 infection Principal investigator(s) B. Eivazi Principal investigator(s) N. Franke & R. Mandic Summary Differentiation among distinct entities Summary The pathogenesis of vascular anomalies within vascular anomalies is essential for proper (VA) of the head and neck area is only incompletely clinical management. Up to date, no specific marker understood. Preliminary immunohistochemical could become established for differential diagnosis. studies point to the presence of human papilloma Glucose-transporter-1 protein (GLUT-1), which is virus (HPV) E6 oncoproteins in nerves and evident in placenta tissue, has been found to be endothelial cells present in VAs. Other groups present also on infantile hemangiomas. Wilms- attributed a pro-angiogenic function to HPV E6, tumor protein 1 (WT-1) has been found to be which is mediated by its ability to upregulate present in hemangiomas and arteriovenous VEGF121. Interestingly, own studies found VEGF121 malformations, whereas a role of D2-40 to be significantly upregulated in VAs. The aim of this (podoplanin) for lymphatic malformations is project is to evaluate if HPV is implicated in the discussed. The aim of this study is to identify and pathogenesis of head and neck VAs. evaluate the role of these markers not only for the Funded by P. E. Kempkes Foundation differential diagnosis, but also for conclusive studies Funding period 2014 – 2015 on the pathogenesis of these entities.
Title The chorion allantoic membrane (CAM) assay as Title Evaluation of artifacts and intracochlear a model system to study vascular anomalies placement of different cochlear electrodes in various Principal investigator(s) R. Mandic, J. Jedelská- radiologic modalities (X-Ray, CBCT, CT and MRI) Keusgen, B. Eivazi, S. Wiegand, U. Bakowsky & J.A. Principal investigator(s) C. Gueldner Werner Summary Phase 1: All patients with a radiological Summary No reliable model systems exist for the dislocation between the scales will undergo further study of vascular anomalies such as arterio-venous investigations. The profile of the intracochlear or lymphatic malformations. For decades, the CAM position of the electrode will be correlated to the assay was successfully used in cancer research, profile of the intraoperative biophysical investigating tumor growth and angiogenesis. The measurements (NRTs, impedances). Phase 2: The aim of this project is to assess the suitability of the possibilities of visualization of the different CAM assay for studies of vascular anomalies. intracochlear positions of the electrodes (vestibular scale, tympanic scale, dislocation between scales) of Title Evaluation of ANCROD in Therapy of the sudden the different radiological tools (X-Ray, CT, CBCT, hearing loss MRI) will be analyzed. Phase 3: The different Principal investigator(s) C. Gueldner electrodes are implanted as full implants into human Summary STUDY PHASE: Phase II. DESIGN: This is a cadaveric heads. To have comparable results, the randomized, double-blind, multicenter, placebo typical different locations of insertion of the controlled, parallel-group phase II proof-of-concept electrode are planned to be performed. So, each study comparing Ancrod treatment versus placebo in electrode will be implanted via cochleostomy, round patients with unilateral sudden sensorineural window and enlarged round window approach.
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Radiological imaging will be performed using understanding of the clinical course, secondly to conventional X-Ray-examination and CT (64 slice, integrate this fact into the therapeutic scheme and Siemens). Afterwards, diameters at different points into the differential diagnosis, and thirdly to improve of the electrodes will be measured in every the safety of surgical procedures on venous diagnostic tool. This will result in a rate of artifacts malformation by early detection of LIC. individual for each combination of electrode and radiologic diagnostic tool. Title Intraperitoneal oxidative stress as an oncolytic Funded by Cochlear Europe immunemodulator Funding period 2014 – 2016 Principal investigator(s) R. Mandic & M. Bette Summary Intraperitoneal oxidative stress effectively Title Candidate genes involved in cisplatin resistance converts the immune response against the of head and neck cancer. papillomavirus-associated rabbit VX2 carcinoma Principal investigator(s) R. Mandic from tumor permissive to tumoricidal and leads to a Summary Sensitivity to chemotherapeutic agents sustainable oncolytic immune response that can be such as cisplatin correlates with the overall survival adoptively transferred. This study aims to further of head and neck cancer patients. This study is dissect the immunological and molecular focusing on the functional characterization of mechanisms underlying the immune recognition of previously identified candidate genes (initial funding VX2 tumor cells leading to tumor regression and how by UKGM) that are differentially expressed in this information can be applied in the treatment of cisplatin-resistant HNSCC cells. These candidate human HNSCC patients. genes could serve as potential therapeutic targets to overcome cisplatin resistance. Title Design and development of a disease-specific questionnaire for the assessment of quality of life in Title Role of adenosine receptors in chemotherapy patients with arteriovenous malformations of the resistance of regulatory T cells in patients with head head and neck and neck cancer Principal investigator(s) A. Zimmermann Principal investigator(s) M. Mandapathil Summary Arteriovenous malformations (AVM) of Summary The aim of this project is to study the role the head and neck are characterized by specific of adenosine receptors in the resistance of symptoms and problems that significantly affect the regulatory T cells (Treg) to chemotherapeutic drugs quality of life and that are not covered by the in HNC patients. Treg maintain profound existing quality of life questionnaires such as immunosuppression in HNC patients, also following bleeding, pulsations, sensations of heat, distortion / chemotherapy, as they persist in the peripheral deformation, paraesthesia, and many more. The aim blood of these patients after treatment. The of our study is to analyze the quality of life of underlying mechanisms are yet unknown, but there patients with AVMs, especially in terms of the is evidence that paracrine adenosinergic effects in question if a specific questionnaire for AVMs is Treg contribute to their chemoresistance. reasonable. Manipulation of this pathway could improve immune responses and therefore prognosis of HNC Title The role of regulatory T cells in the lymphogenic patients. metastasis of patients with head and neck cancer Funded by Foundation Tumorforschung Kopf/Hals Principal investigator(s) M. Mandapathil (Alexander-Karl-Prize) Summary The involvement of immunosuppressive Funding period 2012 – 2013 Treg in the formation of metastasis to the cervical lymph nodes is not fully understood. The frequency Title Significance of the localized intravascular and activity of Treg is increased in cancer patients coagulopathy and marker function of D-dimers in and positively correlate with the disease stage. venous malformations of the head and neck Therefore, it is likely that Treg play a key role in the Principal investigator(s) B. Eivazi formation and occurrence of lymphogenic Summary A size-dependent increase in D-dimer- and metastasis in head and neck cancer. a decrease of fibrinogen levels as a sign of localized Funded by Alfred und Ursula Kulemann Foundation intravascular coagulopathy (LIC) are observed in Funding period 2012 – 2013 extensive venous malformations. Furthermore, the D-dimers are considered as a reliable marker for this particular entity. Since venous malformations of the head and neck are already relevant at much smaller General information about the institute size, the extent of the LIC and the significance of D- dimer as a potential marker are to be clarified. The Research funding 82.307,83 € aim of this study is to identify and evaluate the role of LIC for following purposes: firstly to improve the
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Most important publications adoptively transferable. Clin Cancer Res 20(16):4289- Mandapathil M, Visus C, Finn OJ, Lang S, Whiteside 301. TL (2013) Generation and immunosuppressive functions of p53-induced human adaptive regulatory T cells. Oncoimmunology 2(7):e25514 Contact Details: Jedelská J, Strehlow B, Bakowsky U, Aigner A, Höbel Baldingerstraße, 35043 Marburg, S, Bette M, Roessler M, Franke N, Teymoortash A, Tel.: ++49 (0) 6421-58 62850 Werner JA, Eivazi B, Mandic R (2013) The Director: Professor Dr. Jochen A. Werner chorioallantoic membrane assay is a promising ex vivo model system for the study of vascular anomalies. In Vivo 27(6):701-5
Teymoortash A, Bohne F, Jonsdottir T, Hoch S, Eivazi B, Roessler M, Werner JA, Mandic R (2013) Human papilloma virus (HPV) is not implicated in the etiology of Warthin's tumor of the parotid gland. Acta Otolaryngol 133(9):972-6
Wiegand S, Wiemers C, Murthum T, Zimmermann AP, Bette M, Mandic R, Werner JA (2013) Risk of lymph node metastases after en bloc cold steel, en bloc laser-, and piecemeal laser surgical resection of auricular VX2 carcinoma. Lasers Med Sci 28(4):1137- 41
Makarova G, Bette M, Schmidt A, Jacob R, Cai C, Rodepeter F, Betz T, Sitterberg J, Bakowsky U, Moll R, Neff A, Sesterhenn A, Teymoortash A, Ocker M, Werner JA, Mandic R (2013) Epidermal growth factor-induced modulation of cytokeratin expression levels influences the morphological phenotype of head and neck squamous cell carcinoma cells. Cell Tissue Res 351(1):59-72
Güldner C, Heinrichs J, Weiß R, Eivazi B, Bien S, Teymoortash A, Werner JA, Diogo I (2013) Prospective evaluation of reliability of cone-beam computed tomography in detecting different position of vibroplasty middle ear implants. Clin Otolaryngol 38(3):217-24
Tonigold M, Rossmann A, Meinold M, Bette M, Märken M, Henkenius K, Bretz AC, Giel G, Cai C, Rodepeter FR, Beneš V, Grénman R, Carey TE, Lage H, Stiewe T, Neubauer A, Werner JA, Brendel C, Mandic R (2014) A cisplatin-resistant head and neck cancer cell line with cytoplasmic p53(mut) exhibits ATP-binding cassette transporter upregulation and high glutathione levels. J Cancer Res Clin Oncol 140(10):1689-704
Rossmann A, Mandic R, Heinis J, Höffken H, Küssner O, Kinscherf R, Weihe E, Bette M (2014) Intraperitoneal oxidative stress in rabbits with papillomavirus-associated head and neck cancer induces tumoricidal immune response that is
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Department of Ophthalmology
Chair Professor W. Sekundo Title OCEAN Principal investigator(s) T. Bertelmann Main fields of research Summary A multicentre, open-label, non- Refractive surgery (ReLEX/SMILE) interventional study to observe treatment patterns Lamellar corneal transplantation (DMEK) in patients with wet age-related macular Glaucoma degeneration (wAMD), with visual impairment due Vitreous and vitreoretinal diseases to diabetic macular edema (DME), due to macular edema following retinal vein occlusion (RVO) or due Research projects to chorioidal neovascularization following pathologic myopia (mCNV) with repeated intravitreal injections Title BLUE-RAY of Lucentis® (Ranibizumab) including optional OCT Principal investigator(s) W. Sekundo monitoring over a 24 months observational period Summary Clinical evaluation of the efficiacy of IOL under real life conditions. calculation using raytracing - toric IOLs. Funded by Novartis Pharma GmbH Funded by Zeiss Meditec AG Funding period 2012 – 2016 Funding period 2013 – 2016
Title PRIDE Title PERSEUS Principal investigator(s) T. Bertelmann Principal investigator(s) T. Bertelmann Summary Multicenter 12-months clinical study to Summary A prospective non-interventional study to evaluate efficacy and safety of Ranibizumab alone or assess the effectiveness of aflibercept (Eylea®) in in combination with laser photocoagulation vs. laser routine clinical practice in patients with wet age- photocoagulation alone in proliferative diabetic related macular degeneration. retinopathy. Funded by Bayer Pharma AG Funded by Novartis Pharma GmbH Funding period 2013 – 2014 Funding period 2012– 2014
Title SALT Title CONSTANCE Principal investigator(s) T. Bertelmann Principal investigator(s) T. Bertelmann Summary A 12-month, phase IV, randomized, open Summary This study is a multicenter, prospective, label, multicenter study to compare efficacy of 0.5 observational study to evaluate the long-term safety mg ranibizumab PRN compared to 2 mg aflibercept of OZURDEX® in patients with macular oedema bimonthly intravitreal injections on retinal thickness following central retinal vein occlusion (CRVO) or stability till month 6 of treatment and explore branch retinal vein occlusion (BRVO) or patients with correlated functional outcomes up to month 12 in non-infectious posterior segment uveitis in real- patients with neovascular (wet) age-related macular world clinical practice. degeneration (AMD). Funded by Pharm-Allergan GmbH Funded by Novartis Pharma GmbH Funding period 2012 – ongoing Funding period 2013 – 2015
Title Intraocular fibrinolysis study group Title INJECT Principal investigator(s) T. Bertelmann Principal investigator(s) T. Bertelmann Summary Detection of intravitreal activities and/or Summary Investigation of Jetrea in patients with concentrations of the fibrinolytic system confirmed vitreo-macular traction. components in eyes with diabetic macular edema Funded by Alcon Pharma GmbH and wet age-related macular degeneration. Funding period 2014 – 2017 Funded by IIT, Novartis Pharma GmbH
Funding period 2013 – 2015 Title C12-II
Principal investigator(s) W. Sekundo Title Intraocular opsin study group Summary Clinical evaluation of the femtosecond Principal investigator(s) T. Bertelmann laser system VisuMax© for treatment of hyperopic Summary Detection of intravitreal opsin eyes with lenticule extraction. concentrations in eyes with and without disturbance Funded by Zeiss Meditec AG of the blood-retina-barrier. Funding period 2013 – 2014 Funded by IIT
Funding period 2014 – 2017
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Title Intraocular neurotrophins study group Bertelmann T, Stief T, Sekundo W (2014) Soluble Principal investigator(s) T. Bertelmann opsin is present in human vitreous. Exp Eye Res Summary Detection of intravitreal neurotrophin 121:23-5 concentrations in eyes with and without disturbance of the blood-retina-barrier. Bertelmann T, Schulze S, Bölöni R, Sekundo W, Irle S, Funded by IIT Stief T, Mennel S (2014) Intravitreal vascular Funding period 2014 – 2015 endothelial growth factor. Graefes Arch Clin Exp Ophthalmol 252(4):583-8 Title OCTAVIAN Principal investigator(s) T. Bertelmann Blum M, Flach A, Kunert KS, Sekundo W (2014) Five- Summary Use of optical coherence tomography year results of refractive lenticule extraction. J (OCT) to objectively assess the vitreomacular Cataract Refract Surg 40(9):1425-9 interface. Funded by IIT, Novartis Pharma GmbH Funding period 2014 – 2016 Contact Details: Baldingerstraße 35043 Marburg, Phone:++49 (0) 6421-58 62850 Director: Professor Dr. Walter Sekundo General information about the institute
Research funding 101.259,91 €
Most important publications Blum M, Kunert KS, Voßmerbäumer U, Sekundo W (2013) Femtosecond lenticule extraction (ReLEx) for correction of hyperopia - first results. Graefes Arch Clin Exp Ophthalmol 251(1):349-55
Meyer CH, Kaymak H, Liu Z, Saxena S, Rodrigues EB (2014) Geometry, penetration force, and cutting profile of different 23-gauge trocars systems for pars plana vitrectomy. Retina 34(11):2290-9
Monnereau C, Quilendrino R, Dapena I, Liarakos VS, Alfonso JF, Arnalich-Montiel F, Böhnke M, Pereira NC, Dirisamer M, Parker J, Droutsas K, Geerling G, Gerten G, Hashemi H, Kobayashi A, Naveiras M, Oganesyan O, Orduña Domingo E, Priglinger S, Stodulka P, Torrano Silva J Jr, Venzano D, Vetter JM, Yiu E, Melles GR (2014) Multicenter study of descemet membrane endothelial keratoplasty: first case series of 18 surgeons. JAMA Ophthalmol 132(10):1192-8 van Dijk K, Droutsas K, Hou J, Sangsari S, Liarakos VS, Melles GR (2014) Optical quality of the cornea after Descemet membrane endothelial keratoplasty. Am J Ophthalmol 158(1):71-79
Koss MJ, Hoffmann J, Nguyen N, Pfister M, Mischak H, Mullen W, Husi H, Rejdak R, Koch F, Jankowski J, Krueger K, Bertelmann T, Klein J, Schanstra JP, Siwy J (2014) Proteomics of vitreous humor of patients with exudative age-related macular degeneration. PLoS One 9(5):e96895
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Department of Dermatology and Allergology
Chair Professor M. Hertl Principal investigator(s) M. Hertl & C. Sitaru A. Bender M.D., R. Eming M.D., C. Möbs PhD, W. Summary In this joint project, the immune Pfützner M.D., T. Schmidt PhD mechanisms leading to clinically overt autoimmune diseases will be studied in elderly patients with Main fields of research pruritic dermatoses. Previous studies have shown 1. Autoimmune dermatoses: autoimmune bullous that a significant number of elderly patients have IgG disorders, lichen planus, collagen vascular autoantibodies against the autoantigens of bullous diseases, vasculitides (R. Eming M.D., M. Hertl, pemphigoid, BP180 and BP230, but do not yet fulfill M.D., T. Schmidt, PhD) all the criteria of the autoimmune bullous skin 2. Allergology: respiratory allergies, hymenoptera disorder, bullous pemphigoid venom allergy, immune mechanisms of specific Funded by DFG (He 1602/13-1) – German Research immunotherapy, tolerance induction in allergy, Foundation atopic eczema, drug allergy (W. Pfützner M.D., Funding period 2012 – 2015 C. Möbs PhD) 3. Dermatooncology: Human malignant melanoma Title Clinical Trial „Effect of simvastatin in in basic and clinical research, focusing on combination with a superpotent topical immune modulation by regulatory CD4+ T cells corticosteroid in bullous pemphigoid“ and immunotherapy which might result in Principal investigator(s) M. Hertl, M. Goebeler & M. advanced vaccine strategies (A. Bender M.D.) Behzad 4. Psoriasis (C. Möbs PhD) Summary In this tri-center trial (Marburg, Würzburg, Wuppertal), the anti-inflammatory properties of the statins will be investigated in a cohort of patients Research projects with bullous pemphigoid. The clinical efficacy of the statins will be evaluated by the cumulative dose of Autoimmune bullous disorders topically applied clobetasol until clinical remission is Title Charakterisierung regulatorischer T-Zellen beim reached. Pemphigus Funding period 2013 – 2015 Principal investigator(s) R. Eming & M. Hertl Summary Pemphigus is probably among other factors a result of a dysregulation of peripheral Title Preclinical validation, development and clinical tolerance. The role of autoantigen specific CD4+ testing of a tolerance inducing immunotherapy regulatory T-cells in maintaining peripheral tolerance (phase Ib) in pemphigus vulgaris to the autoantigen desmoglein 3 in pemphigus is Principal investigator(s) M. Hertl & C. Schade- investigated in this project. Brittinger Funded by DFG (He 1602/7-1, 7-2, 7-3) – German Summary This proposal deals with the creation of an Research Foundation extensive project proposal for the early Funding period 2004 – 2014 development and testing of an innovative treatment of the potentially life-threatening autoimmune Title Efficacy and safety of adjuvant disease pemphigus vulgaris. The central project goal immunoadsorption in pemphigus vulgaris and is to establish a balanced consortium that combines pemphigus foliaceaus. A randomized, prospective, all expertise necessary for the successful multi-center, parallel-group study (IA-Pem-study) implementation of this innovation project with a Principal investigator(s) R. Eming project strategy that meets the complex technical Summary Aim of the study is to investigate whether and regulatory requirements involved in the adjuvant immunoadsorption is superior to standard development of a nanoparticle-based treatment. immunosuppressive treatment in inducing clinical The project plan provides for two stages: at first, remission in pemphigus. safety and efficacy of the application of proteins Funded by DFG (Em 80/2-1) / BMBF – German coupled with nanoparticles is examined in an HLA- Science Foundation / Federal Ministry of Education transgenic mouse model before it will then be and Research examined in pemphigus patients. According to the Funding period 2010 – 2015 results in pemphigus, the nanoparticle-based immunotherapy may also be an option for the Title Entwicklung pathogener Autoimmunreaktionen specific treatment of other autoimmune diseases in beim bullösen Pemphigoi humans.
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Funded by BMBF (01EK1418) – Federal Ministry of of membrane proteins such as ATP-binding cassette Education and Research sub-family A member 12 (ABCA12), are addressed in Funding period 2014 this project. Funded by Internal Funding of the Faculty Title Rolle der Flotilline bei der Zell-Zelladhäsion in Funding period 2012 – 2014 Epithelzellen Principal investigator(s) R. Eming & M. Hertl & R. Tikkanen Summary Cell-cell adhesion plays an important role in the development and maintenance of multicellular structures. This project focuses on the molecular pathways involved in the assembly and maintenance of two major adherence structures in the epidermis, i.e. desmosomes and adherence junctions. The role of lipid raft-associated proteins called flotillines in cell-cell adhesion of epidermal keratinocytes is investigated. Previous results suggest that flotillines interact with the cell adhesion molecule gamma-catenin; furthermore the expression of adhesion proteins in flotilline-2 knock- out mice is altered. One goal of this collaborative project is to investigate whether flotillines demonstrate a regulatory function in the assembly of desmosomes and whether they might play a role Fig. 1: In vivo induction of pathogenic IgG autoantibodies in the pathogenesis of the blistering autoimmune in an HLA class II transgenic pemphigus mouse model disorder, pemphigus. Funded by Von-Behring-Röntgen Foundation Title Depression und Lebensqualität bei Pemphigus- Funding period 2012 – 2015 Patienten Principal investigator(s) R. Eming & R. Dodel Title Rolle extra- und intradesmosomaler Cadherine Summary Pemphigus represents a rare chronic beim Pemphigus organ-specific autoimmune disorder affecting skin Principal investigator(s) M. Hertl, R. Eming, R. Jacob and mucous membranes. Due to severe blister & J. Hoyer formation and widespread erosions pemphigus Summary The loss of cell-cell adhesion of epidermal patients are heavily impaired in their daily life. Only keratinocytes is a pathogenic hallmark in pemphigus, few investigations have addressed the aspects of an organ-specific autoimmune disease of the skin quality of life and psychiatric disorders such as and mucous membranes. The exact molecular depression in pemphigus patients so far. However, mechanisms leading to the loss of keratinocyte previous results suggest that these parameters are adhesion are still incompletely understood. This severely affected by the autoimmune disease and its project aims at characterizing the role of intra- and therapy, respectively. The aim of this nation-wide extradesmosomal cadherins, especially desmoglein cross-sectional study is to characterize the incidence, 1, 3 and desmocollin 1, 3 in the process of the severity and the treatment options of depressive keratinocyte detachment. The hypothesis that disorders in a cohort of pemphigus patients. Various extradesmosomal cadherins might provide a crucial parameters such as quality of life, comorbidities, target in the autoantibody response in pemphigus pemphigus disease activity, treatment and severity thereby interrupting the constant recruitment of of depression (Beck Depression Inventory (BDI-II) are extradesmosomal cadherins into the desmosome is investigated. being investigated. Moreover, the function of E- Funded by UKGM – University Medical Centre cadherin, a non-desmosomal important component Giessen / Marburg of adhesion junctions, in the process of keratinocyte Funding period 2011 – 2013 detachment in pemphigus is examined. Molecular events such as Src-signaling pathways and Title Validation of serological diagnostics in the alterations in two-pore domain potassium channels detection of IgG autoantibodies against human (K2P-TREK/TWIK) in epidermal keratinocytes after collagen type VII in epidermolysis bullosa acquisita binding of pemphigus autoantibodies are (EBA) investigated in cultured keratinocytes. Finally, Principal investigator(s) M. Hertl & M. Behzad changes in the cytoskeleton of epidermal Summary The purpose of this project is to validate in keratinocytes and alterations in the polarization of vitro diagnostic products for epidermolysis bullosa these epithelial cells, e.g. changes in the distribution acquisita (EBA). It aims at comparing the sensitivity
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Clinical Institutions and specificity of four different diagnostic Title Charakterisierung ASIT-induzierter, procedures in the detection of serum IgG blockierender IgG-Antikörper bei Hymenopteren- autoantibodies against human collagen type VII. The giftallergien analysis includes validation of the MESACUP anti- Principal investigator(s) C. Möbs type VII collagen Test for diagnosis and monitoring Summary Cross-sectional study to analyze the disease activity of EBA. occurrence and long-term maintenance of Funded by MBL, Nagoya, Japan hymenoptera venom-specific IgG blocking antibodies Funding period 2014 – 2016 after successful allergen-specific immunotherapy
(ASIT). Evaluation of the ASIT-induced allergen
blocking capacity of IgG antibodies and correlation of Allergology its inhibitory activity with clinical tolerance. Title Cellular and humoral mechanisms of specific Funded by Internal Funding of the Faculty immunotherapy (SIT) of respiratory type-I-allergies Funding period 2014 – 2016 Principal investigator(s) W. Pfützner & M. Hertl,
Summary Characterization of humoral (e.g. specific Title Modulation humoraler und T-zellulärer antibody concentrations, blocking capacity) and Faktoren durch allergenspezifische Immuntherapie cellular parameters (e.g. specific T cell and cytokine (ASIT) mit einer rekombinanten, hypoallergenen responses) in patients with birch pollen allergy Vakzine treated with specific immunotherapy. Comparison of Principal investigator(s) C. Möbs & W. Pfützner alternative treatment routes (subcutaneous, Summary Characterization of a peptide carrier- sublingual) and allergen preparations (native based, recombinant, hypoallergenic grass pollen allergen, modified allergoids). allergy vaccine in comparison to allergen-specific
immunotherapy with conventional, native grass SIT post-SIT pollen extract. Analysis of effector and regulatory T
cell subsets and allergen-specific antibody
IgE concentrations in peripheral blood and nasal IgG4 secretion of grass pollen allergic patients. Th2 Funded by UKGM – University Medical Center
Tr1 Giessen/Marburg) m0 m6 m18 m30 m42 m54 Funding period 2014 – 2016 Fig.: Specific immunotherapy (SIT)-induced alterations in patients with birch pollen allergy Title Impaired immune regulation in hymenoptera Funded by DFG HE 1602/10-1, SFB/TR22 – German venom allergy and its correction by specific Research Foundation, Transregional Collaborative immunotherapy Research Centre 22 Principal investigator(s) W. Pfützner Funding period 2007 – 2009; 2009 – 2013, 2013 – Summary Analysis of immunological tolerance 2014 induction (i.e. alterations in allergen-specific antibody concentrations and T cell subsets) in Title B-zelluläre Regulation der Allergentoleranz bei patients with bee and wasp venom allergy treated by spezifischer Immuntherapie IgE-vermittelter allergen-specific immunotherapy and impact of Respirationsallergien treatment on patients’ quality-of-life Summary Aim of this study is to characterize if (questionnaires). allergen-specific B cells serve as mediators of allergen tolerance by production of allergen-blocking Title Immunological pathomechanisms of delayed- antibodies and/or secretion of regulatory cytokines type allergies induced by beta-lactam antibiotics during the course of allergen-specific Principal investigator(s) W. Pfützner immunotherapy (ASIT). Furthermore, the role of Summary Identification of distinct subsets of beta- both different modes of allergen application lactam specific T cell frequencies in patients with (subcutaneous vs. sublingual ASIT) in modifying the B drug-induced delayed-type-hypersensitivity. cellular immune response and allergen-specific Subcategorization of T cell-mediated drug-induced memory B cells in maintaining long-term tolerance is type-IV-reactions according to their cytokine pattern addressed. (type-IVa to type-IVd). Principal investigator(s) W. Pfützner & C. Möbs, Funded by DFG (PF 344/3-1/MO 2076/3-1) – Title Diffusion Tensor Imaging (DTI) in patients with German Research Foundation atopic eczema Funding period 2014 – 2017 Principal investigator(s) W. Pfützner Summary Characterization of neuronal mechanisms in the pathogenesis of atopic eczema and their
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Clinical Institutions correlation to defined genetic and immunological parameters. Title MO25616 (Vismodegib) “A single arm, open- label, phase II, multicentre study to assess the safety of vismodegib (GDC-0449) in patients with locally Non-investigator initiated clinical trials: advanced or metastatic basal cell carcinoma (BCC); Title APPLES “A prospective pediatric longitudinal MO25515 (Vemurafenib) “An open-label, evaluation to assess the long-term safety of multicenter expanded access study of RO5185426 in tacrolismus ointment for the treatment of atopic patients with *metastatic melanoma* dermatitis” (FHI 03-0-161/FG-506-06-37) Principal investigator(s) A. Bender Principal investigator(s) W. Pfützner Funded by Roche Funded by Astellas Title IMAGE (CA184143) “A Multi-National, Title XOLAIR Q4883g “A phase III, multicenter, Prospective, Observational Study in Patients with randomized, double-blind, placebo-controlled safety Unresectable or Metastatic Melanoma study of xolair (omalizumab) in patients with chronic Principal investigator(s) A. Bender idiopathic urticaria who remain symptomatic despite Funded by Bristol-Myers Squibb treatment with H1 antihistamines, H2 blockers and/or leucotriene receptor antagonists” Title PO-Studie Melanom “Die neuroimmuno- Principal investigator(s) W. Pfützner logischen Auswirkungen von Stress und ihre Rolle Funded by Genentec beim Melanom (Psychoonkologie-Studie)“ Principal investigator(s) A. Bender Title BIOMAY CS-BM-32-003 “Phase IIb study on the Funded by UKGM – University Medical Centre safety and efficacy of BM32, a recombinant Giessen / Marburg hypoallergenic vaccine for immunotherapy of grass pollen allergy” Principal investigator(s) W. Pfützner Psoriasis Funded by Biomay AG Title CD4+CD25+ regulatorische T-Zellen bei Psoriasis vulgaris Title Allergovit “Double-blind phase IV multicenter Principal investigator(s) A. Jacobi clinical trial to evaluate and compare specific and Summary Characterization of the impact of biologics non-specific effects of SCIT by use of an on the cellular immune response in psoriasis under Environmental Challenge Chamber after treatment treatment with TNF-α blockers and Fumaric acid with Allergovit® grasses or Allergovit® birch in esters. patients with grass and birch pollen allergy” Funded by Biogen Idec Principal investigator(s) W. Pfützner Funding period 2014 Funded by Allergopharma Title Systemische Entzündungsprozesse bei Title AWARE „Nicht-interventionelle chronische chronisch entzündlichen Erkrankungen der Haut - Urtikaria-Studie zur Erfassung von klinischen Daten Psoriasis aus der täglichen Praxis“ Principal investigator(s) A. Jacobi, R. Mößner & M. Principal investigator(s) W. Pfützner P. Schön Funded by Novartis Funded by Universitätshautklinik Göttingen Funding period 2012 – 2016
Dermatooncology Title Epidemiologische Studie “Predictors of psoriasis Non-investigator initiated clinical trials for on response to systemic therapy (PREDICT) treatment of early and progressing malignant Principal investigator(s) A. Jacobi melanoma: Funded by AbbVie Deutschland Funding period 2012 – 2016 Title DERMA trial ”Adjuvant immunotherapy with MAGE-A3 in melanoma (Stage IIIB-IIIC)”; COMBI-AD trial “A Phase III Randomized Double Blind Study of Dabrafenib (GSK2118436) in COMBInation With General information about the institute Trametinib (GSK1120212) Versus Two Placebos in the ADjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Research funding 1.281.920,57 € Resection” Principal investigator(s) A. Bender Funded by Glaxo Smith Kline
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Most important publications Contact Details: Subbarayal B, Schiller D, Möbs C, de Jong NW, Ebner Baldingerstraße 35043 Marburg, C, Reider N, Bartel D, Lidholm J, Pfützner W, Gerth Phone:++49 (0) 6421-58 66280 van Wijk R, Vieths S, Bohle B (2013) Kinetics, cross- Director: Professor Dr. Michael Hertl reactivity, and specificity of Bet v 1-specific IgG4 antibodies induced by immunotherapy with birch pollen. Allergy 68(11):1377-86
Colliou N, Picard D, Caillot F, Calbo S, Le Corre S, Lim A, Lemercier B, Le Mauff B, Maho-Vaillant M, Jacquot S, Bedane C, Bernard P, Caux F, Prost C, Delaporte E, Doutre MS, Dreno B, Franck N, Ingen- Housz-Oro S, Chosidow O, Pauwels C, Picard C, Roujeau JC, Sigal M, Tancrede-Bohin E, Templier I, Eming R, Hertl M, D'Incan M, Joly P, Musette P (2013) Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response. Sci Transl Med 5(175):175ra30
Kurrle N, Völlner F, Eming R, Hertl M, Banning A, Tikkanen R (2013) Flotillins directly interact with γ- catenin and regulate epithelial cell-cell adhesion. PLoS One 8(12):e84393
Rafei-Shamsabadi D, Müller S, Pfützner W, Spillner E, Ruëff F, Jakob T (2014) Recombinant allergens rarely allow identification of Hymenoptera venom-allergic patients with negative specific IgE to whole venom preparations. J Allergy Clin Immunol 134:493-494 Letter to the Editor
Schmidt T, Sitaru C, Amber K, Hertl M. (2014) BP180 and BP230 specific IgG autoantibodies in pruritic disorders of the elderly - a pre-clinical stage of bullous pemphigoid? Br J Dermatol 171(2):212-9
Eming R, Hennerici T, Bäcklund J, Feliciani C, Visconti KC, Willenborg S, Wohde J, Holmdahl R, Sønderstrup G, Hertl M (2014) Pathogenic IgG antibodies against desmoglein 3 in pemphigus vulgaris are regulated by HLA-DRB1*04:02-restricted T cells. J Immunol 193(9):4391-9
Nagel A, Möbs C, Raifer H, Wiendl H, Hertl M, Eming R (2014) CD3-positive B cells: a storage-dependent phenomenon. PLoS One 9(10):e110138
Wambre E, DeLong JH, James EA, Torres-Chinn N, Pfützner W, Möbs C, Durham SR, Till SJ, Robinson D, Kwok WW (2014) Specific immunotherapy modifies allergen-specific CD4(+) T-cell responses in an epitope-dependent manner. J Allergy Clin Immunol 133(3):872-9.e7
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Department of Neurology
disorders (alpha-synucleinopathy; REM sleep th Chair Professor W. H. Oertel (until June 30 , 2014) behavior disorder (RBD), Parkinson disease, multiple Professor R. Dodel (since July 1st, 2014) system atrophy(MSA), dementia Lewy body type(DLB); tauopathies; progressive supranuclar Apl. Prof. Dr. med. K. Bürk palsy) - hyposmia, depression, stomach-gut function Methods: cell culture, stem cell research, animal Therapeutic Research and Dementia models for Parkinson disease, microbiomics, (AG Prof. Dodel) neuropsychology, autonomic, oculomotor, German Parkinson Study Group sensomotor control, phase II and III randomized (PD Dr. Eggert) controlled therapeutical trials, magnetresonance Hertie-Senior Research Professorship tomography (VBM, resting state, diffusion tensor, (AG Prof. Oertel) functional MRI, others), nuclear medicine imaging Movement Disorders - Experimental (SPECT, PET), long term follow-up Neurology (PD Dr. Ries/PD Dr. Neurological sleep research: restless legs syndrome, narcolepsy, REM sleep behavior disorder Depboylu/Prof. Höglinger) Working Group on Clinical and Movement Disorders - Experimental Neurology (PD Experimental Epileptology Dr. Ries/PD Dr. Depboylu/Prof. Höglinger) (AG Prof. Rosenow) Mechanisms of endogenous brain repair processes. Neuro-Oncology (Prof. Strik) Experimental modeling of neurodegeneration and Clinical Neuroimmunology Group study of endogenous neurogenesis. Development of (AG PD Dr. Tackenberg) novel protective or restorative treatments.
Working Group on Clinical and Experimental Main fields of research Epileptology (AG Prof. Rosenow) Apl. Prof. Dr. med. K. Bürk Clincal and experimental epileptology, epilepsy Movement disorders, especially ataxic, spastic and genetics, cognitive neurology, neuroimaging motor hyperkinetic movement disorders including cortex physiology, The role of micro RNA, Spinocerebellar ataxias, recessive ataxias, spastic neuropeptides and cytokines in pathopysiology, paraplegias and Huntington´s disease (HD). treatment and prevention of epilepsy, health Description of phenotypical presentations and economy. genotyping including identification of new mutations causing hereditary movement disorders. Neuro-Oncology (Prof. Strik) Glioma biology; CSF involvement in neoplastic Therapeutic Research and Dementia (AG Prof. diseases; Supportive care in neurooncology Dodel) Autoimmunity in neurodegenerative disorders; Clinical Neuroimmunology Group (AG PD Dr. Translational research; investigator-initiated clinical Tackenberg) trials; Health-economic evaluations in neurological Treatment predictors for Multiple Sclerosis; disorders Immunotherapy of Multiple Sclerosis and other neurological autoimmune diseases; T-cell/B-cell German Parkinson Study Group (PD Dr. Eggert) interaction in autoimmunity Design, execution and analysis of pharmacological multicenter trials on motor and non-motor symptoms in patients with Parkinson’s disease and Research projects atypical Parkinson-Syndromes. Development of new Apl. Prof. Dr. med. K. Bürk study designs for disease modifying or neuroprotective agents in Parkinson’s disease Title Identification of novel mutations causing hereditary ataxia Hertie-Senior Research Professorship (AG Prof. Principal investigator(s) K. Bürk in cooperation with Oertel) Prof. Dr. C. Zühlke, University of Lübeck Neurodegeneration - neuroprevention - translational Summary Phenotypical description of patients with neurology: new preclinical diagnostic procedures, hereditary ataxias and identification of novel disease modifying and neuropreventive therapy underlying mutations and their pathogenic impact research: on prodromal stages of neurodegenerative
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Title EFACTS: European Friedreich Ataxia Consortium MRI studies. It is our aim to study the evolution of of Translational Studies dementia in PD, to determine the conversion rate to Principal investigator(s) K. Bürk, multicenter study, PDD, and to identify clinical, biochemical and genetic principal investigator Prof. Dr. M. Pandolfo, risk factors. University of Brussels and Prof. Dr. J. B. Schulz, Funded by BMBF – Federal Ministry of Education University of Aachen and Research Summary EFACTS assembles a body of expertise to Funding period 2011 – 2017 adopt a translational research strategy for the rare autosomal recessive Friedreich’s ataxia (FRDA). This Title Health Service Analysis in Patients with project aims to establish a European FRDA database, advanced Parkinson-Syndrome linked to a bio bank, define a panel of clinical Principal investigator(s) J.-P. Reese & R. Dodel assessment tools and to build on the knowledge Summary The aim of the study is to get conclusion base of frataxin structure and function. about the actual health care situation for patients Funded by EU FP7 – European Union with advanced Parkinson-Syndrom in Germany and Funding period 2011 – 2015 possible use of alternative treatment options next to oral polytherapy. Title RISCA: Risk of spinocerebellar ataxia Funded by Abbott Arzneimittel GmbH Principal investigator(s) K. Bürk, multicenter study, Funding period 2012 – 2013 principal investigator Prof. Dr. M. Pandolfo, University of Brussels and Prof. Dr. J. B. Schulz, Title Cloning, Expression and Efficacy Evaluation of University of Aachen Naturally Occurring Autoantibodies against beta- Summary Prospective observational study of Amyloid individuals at risk for the most common SCA Principal investigator(s) J.-P. Bach & R. Dodel disorders, SCA1, SCA2, SCA3 and SCA6 (RISCA). The Summary There is increasing evidence that nAbs are study aims to define the incidence of disease playing an important role in the development of manifestation in mutation carriers, clinical signs neurodegenerative disorders. To date, not much is precede the onset of manifest ataxia, the prevalence known regarding the development and physiological and incidence of preceding signs. and pathophysiological role of nAbs. The aim is to Funded by Former FP6 project isolate B-cells responsible for producing nAbs-Aβ, Funding period No financial support the cloning of these autoantibodies and to test their efficacy in respective models. Title Enroll-HD Funded by Baxter Healthcare Principal investigator(s) K. Bürk, multicenter study, Funding periods 2012 – 2015 principal investigator Prof. Dr. B. Landwehrmeyer, Title Double-blind, randomized, two-arm study of University of Ulm the efficacy of bupropion in the treatment of apathy Summary Enroll-HD is a longitudinal, observational, in patients with Alzheimer's disease (APA-AD) multinational study that will integrate two existing Principal investigator(s) R. Dodel Huntington's Disease (HD) registries, REGISTRY in Summary This multicenter-double-blinded Europe and COHORT in North America and Australia, randomized clinical trial investigates the effect of while also expanding to include sites in Latin America buproprion on apathy in patients with Alzheimer’s and Asia. This database will serve as a basis for disease. future studies aimed at developing tools and Funded by BMBF, through study centre Bonn – biomarkers for progression and prognosis. Federal Ministry of Education and Research Funded by CHDI Foundation Funding period 2012 – 014 Funding period 2014, unlimited Title Multi-site randomised controlled REDALI-DEM trial. The effects of structured Relearning methods Therapeutic Research and Dementia – on Daily Living task performance of persons with AG Prof. Dodel Dementia Principal investigator(s) R. Dodel Title Dementia in Parkinson’s disease: Future Summary To assess the efficacy and safety of Challenges (Landscape) errorless learning hypothesizing a significant Principal investigator(s) R. Dodel difference in the task performance scale 1, 6 and 16 Summary The consortium established a large cohort weeks after treatment completion in favour of the of patients with PD/PDD. The patients will undergo experimental group with at least moderate effect repeated clinical examination, detailed sizes. neuropsychological testing including investigation of Funded by BMBF, through study centre Freiburg– cognitive reserve as well as morphological/functional Federal Ministry of Education and Research Funding period 2012 – 2015
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Title Development and Validation of an Instrument movement dysfunction in PD-patients was to forecast Assessments of Rehabilitation after conducted. Proximal Femur Fractor (Reprof) Funded by Pharmaceutical industry, Willy Robert Principal investigator(s) B.Bücking & R. Dodel Pitzer Foundation, Hessen Funded by UKGM –University Hospital Giessen / Funding period 2013 – 2014 Marbrug Funding period 2013 Hertie-Senior Research Professorship – AG Title Long-term Follow-up on a Cohort of Parkinson Prof. Oertel in cooperation with PD Dr. Patients Depboylu and PD Dr. Ries Principal investigator(s) M. Balzer-Geldsetzer & R. Dodel Title Effect of nicotinergic drugs and other Summary The project is a naturalistic observational compounds on the toxicity of alpha-synuclein multi-center cohort study (follow-up at 6 years post overexpression onto dopaminergic neurons in a baseline) in a stratified sample of outpatients (office- protein-aggregation mouse-model of Parkinson based neurologists) with Parkinson’s disease. The disease objectives are to re-evaluate this large cohort and to Principal investigator(s) W. H Oertel re-characterize these patients in a standardized Summary To test the potentially disease-modifying manner by clinical and neuropsychological testing as effect of nicotinergic drugs (and other compounds) well as assessment of health-related quality of life on the protein aggregation induced unilateral and depression. Parkinson model in mouse – developing an animal Funded by International Parkinson Fonds (IPF) test model for new therapeutical developments. Funding period 2013 – 2014 Funded by Hertie-Senior-Research Professorship and
Novartis Deutschland GmbH Title Joint Programme - Neurodegenerative Disease Funding period2013 – 2015 Research. Care for Late Stage Parkinsonism (Clasp)
Principal investigator(s) R. Dodel (in Germany) Title Pupillary assessment as an indicator of brain Summary The aim of this project is to evaluate the stem function in REM-sleep behavior disorder (RBD = needs and provision of care for patients with late prodromal Parkinson’s disease (PD)), Parkinson stage Parkinsonism and their carers in six European disease (PD) and healthy control. countries, compare the effectiveness of different Principal investigator(s) W. H. Oertel health and social care systems, and to lay the Summary To develop a test for the function of brain foundation for improved outcomes in this stem nuclei in neurodegenerative disorders population. Funded by DFG – German Research Foundation, Funded by BMBF – Federal Ministry of Education International Research Training Group - IRTG and Research Funding period 2013 – 2016 Funding period 2014 – 2017
Title Real time video MRI imaging of gastric motility
in REM-sleep behavior disorder (RBD = prodromal German Parkinson Study Group – PD Dr. Eggert Parkinson’s disease (PD), de novo PD and healthy Pharmacological multicenter trials on motor and controls non-motor symptoms in patients with Parkinson’s Principal investigator(s) W. H. Oertel disease and atypical Parkinson-Syndromes Summary To analyse the gastric motility in vivo Impact of patient education and psychological without a radioactive method in neurodegenerative factors in Parkinson’s disease quality of life disorders as a indicator for affection of the motor Evaluation of jaw movement dysfunction related to dorsal nucleus of the vagal nerve. Parkinson’s disease Funded by International Parkinson Fonds (IPF)
Funding period 2012 – 2014 Title German Parkinson Study Group, multicenter trials on Parkinson’s disease Title REM-PET - Fluorodesoxy-Glucose-Positron- Principal investigator(s) K. Eggert & H. Pape Emissios-Tomography (FDG-PET) – differential Summary The GPSG has established as one of the diagnostic study between alpha-synucleinopathies – leading groups in Europe for conducting industry- predictive value of FD-PET (pilot study) for sponsored clinical trials and investigator-initiated conversion of RBD to PD trials. In 2013/2014 numerous controlled trials Principal investigator(s) W. H Oertel &, Prof. Klaus assessing new compounds were performed. Leenders, (Groningen, Holland Studies on the impact of patient education and Summary recognition of “specific patterns of glucose psychological factors in PD quality of life were consumption in the CNS” in alpha-synucleinopathies carried out. Furthermore, an evaluation of jaw
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(RBD, PD DLB, MSA) as a differential indicator and dopaminergic stimulation can modulate the survival predictor for conversion from RBD to PD, MSA or and cell fate of neural stem cells in the olfactory bulb DLB in an acute mouse model of PD. Funded by International Parkinson Fonds (Dutch- Funded by Pharmaceutical Industry German-study) (IPF) Funding period 2010 – 2013 Funding period 2013 – 2015 Title Effect of neuregulin-1β1 in MPTP mouse Title CouragePD - genetic-environmental analysis of models of Parkinson's disease risk factors of Parkinson disease Principal investigator(s) V. Ries, C. Depboylu & G. Principal investigator(s) T. Gasser, Tübingen Höglinger Summary providing biosamples for a large scale Summary Extracellular domain of neuregulin-1β1 analysis of risk factor genes of Parkinson disease – in (Nrg1β1), a nerve growth and differentiation factor, relation to environmental factors. passes the blood-brain barrier and rescues Funded by Joint Programming Neurodegeneration dopaminergic neurons of substantia nigra in the 6- (JPND-EU) hydroxydopamine-mouse model of Parkinson's Funding period 2014 – 2016 disease (PD). In another toxin-based mouse model of PD. We found that Nrg1β1 significantly reduced the Title PPMI – Parkinson progression marker initiative loss of nigral dopaminergic neurons in both Principal investigator(s) K. Marek, New Haven, USA intoxication paradigms. Neuroprotective properties Summary Search for biomarkers in early motor stage of Nrg1β1 on nigral dopaminergic neurons are Parkinson patients specifically mediated by ErbB4 as revealed through Funded by Michael J Fox Foundation (MJFF) the study of ErbB4 knockout mice. In conclusion, Funding period2013 – 2016 systemically administered Nrg1β1 protects midbrain dopaminergic neurons against this PD-related toxic Title PPPMI-RBD – prodromal Parkinson progression insult. Thus, Nrg1β1 may have a benefit in the marker initiative treatment of PD patients. Principal investigator(s) W. H. Oertel, G. Mayer and Funded by Pharmaceutical industry, UKGM K. Marek, New Haven, USA Funding period 2011 – 2013 Summary Search for biomarkers in prodromal stage Parkinson patients, i.e. REM-sleep behavior disorder (RBD Working Group on Clinical and Experimental Funded by Michael J Fox Foundation (MJFF) Epileptology – AG Prof. Rosenow Funding period 2013 – 2015 Title EpimiRNA: Micro-RNA in the pathophysiology, Title Nicotine patch (NIC-PD) in de novo Parkinson’s treatment and prevention of epilepsy disease (www.epimirna.eu) Principal investigator(s) W. H Oertel Principal investigator(s) F. Rosenow; K. M. Klein; S. SummaryTesting the potentially disease modifying Knake, A. Strzelczyk, K. Menzler, B. Norwood & S. effect of nicotine on the progression of early (de Bauer novo) Parkinson patients – double blind placebo Summary EpimiRNA: Through highly collaborative, controlled randomized clinical trial inter-disciplinary and inter-sectorial research, Funded by International Parkinson Fonds (IPF), EpiMiRNA will explain the mechanism by which Michael J Fox Foundation (MJFF), German Parkinson miRNAs contribute to epileptogenesis, characterize Study Group (German-USA-trial) genetic variation of miRNA in patients, evaluate Funding period 2013 – 2016 seizure-suppressing effects of miRNAs in experimental models, identify novel miRNA modulatory molecules as potential future Movement Disorders - Experimental Neurology therapeutics, and develop miRNAs as prognostic PD Dr. Ries/PD Dr. Depboylu/Prof. Höglinger markers to identify patients who respond to novel, non-pharmacological therapeutic interventions Title Modulation of adult neurogenesis in the including brain-stimulation. olfactory bulb in a rodent toxin model of Parkinson`s Funded by EU within FP7 (Grant agreement number disease 602130) – European Union Principal investigator(s) V. Ries, C. Depboylu & G. Funding period 2013 – 2018 Höglinger Summary Dopamine depletion in the regions of Title EuroEPINOMICS-RES: Genetics of rare epilepsy adult neurogenesis leads to a reduction of newborn syndromes (www.euroepinomics.org) stem cells in the adult mammalian brain. In this study we investigated, if direct or indirect
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Principal investigator(s) F. Rosenow; K. M. Klein; S. Funded by BMBF – Federal Ministry of Education Knake, A. Strzelczyk, K. Menzler, B. Norwood & S. and Research Bauer Funding period 2012 – 2015 Summary EuroEPINOMICS-RES: The strategy of this RES-CRP is to create a 4-stage pipeline for tackling Title T-cell/B-cell interactions in antibody dependent the genetics of RES starting with (1) sample autoimmune diseases (Myasthenia gravis, CIDP) collection and systematic assessment of phenotypic Principal investigator(s) B. Tackenberg data, (2) screening of known genes, (3) novel gene Summary Activated epitope specific Th-cells provide discovery, by genome-wide screening for novel signals to B lymphocytes for differentiation and genetic risk factors using high-throughput CNV subsequent antibody production by direct analysis and Next-Generation Sequencing and (4) interaction through receptor/ligand systems co- genotype-phenotype correlation/diagnostic mediated by members of the TNF super-family guidelines / functional studies. crucial for survival signalling and apoptosis. Funded by DFG – German Research Foundation and Autoantibody mediated autoimmune diseases (MG; ESF (RO 3396/2-1) CIDP) miss regulated Th-cell activation and migration Funding period 11-2011 to 6-2014 which might lead to positive feedback through TC/ BC interaction resulting in auto-antibody production. Funded by various Neuro-Oncology – Prof. Strik Funding period 2013 – ongoing
Title Internet-based registry of brain tumors and Title Prospective identification and biomaterial neoplastic meningitis characterization of a cohort with active disease using Principal investigator(s) H. Strik 1.5 T vs. 3.0 T MRI in RR-MS under standard immune Summary Primary CNS neoplasms and neoplastic treatment meningitis, neoplastic CSF involvement, are rare. Principal investigator(s) B. Tackenbeg Building up a solid database on treatment results Funded by Industry with a sufficient size of cases even in subgroups Funding period 2013 – 2016 requires a multicentric registry. We are designing an internet-based registry on CNS neoplasms with Title Functional anatomic correlates of working- special respect on neoplastic meningitis that enables memory, interhemispheric interactions, visual to document cases within an international network motion and motor functions in 3.0 T fMRI during of interested centres. fampridine treatment in Multiple Sclerosis patients Funded by Barbara und Wilfried Mohr Fouondation; with concomitant cognitive impairment and motor Medac GmbH; Mundipharma; Riemser Pharma dysfunction Funding period 2011 – 2016 Principal investigator(s) B. Tackenberg Funded by Industry Funding period 2012 – 2015 Clinical Neuroimmunology Group – AG PD Dr. Tackenberg
Title Clinical Trial Center Neuroimmunology General information about the institute Principal investigator(s) B. Tackenberg Summary External (industrial sponsored) and Research funding 4.706.463,29 € internal Phase I-III RCTs were conducted and performed on the basis of the Marburg Outpatient
Neuroimmunology Clinic (MONC) with its 5,500 patient contacts per year. Most important publications Funded by Industry Jacobi H, Reetz K, du Montcel ST, Bauer P, Mariotti C, Funding period 2008 – ongoing Nanetti L, Rakowicz M, Sulek A, Durr A, Charles P, Filla A, Antenora A, Schöls L, Schicks J, Infante J, Kang Title Krankheitsbezogenes Kompetenznetzwerk JS, Timmann D, Fabio RD, Masciullo M, Baliko L, Multiple Sklerose (KKNMS) Melegh B, Boesch S, Bürk K, Peltz A, Schulz JB, Principal investigator(s) B. Tackenberg (local) Dufaure-Garé I, Klockgether T (2013) Biological and Summary The Clinical neuroimmunology Group clinical characteristics of individuals at risk for Marbrug is member of the KKNMS and participates spinocerebellar ataxia types 1, 2, 3, and 6 in the in the nationwide 10-year prospective early MS longitudinal RISCA study: analysis of baseline data. Cohort study (n=1,100) and its treatment registry Lancet Neurol 12:650-8 project “REGIMS”. Wenning GK, Geser F, Krismer F, Seppi K, Duerr S, Boesch S, Köllensperger M, Goebel G, Pfeiffer KP,
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Barone P, Pellecchia MT, Quinn NP, Koukouni V, The International League Against Epilepsy Fowler CJ, Schrag A, Mathias CJ, Giladi N, Gurevich T, Consortium on Complex Epilepsies* *Anney RJL, Dupont E, Ostergaard K, Nilsson CF, Widner H, Oertel Avbersek A, Balding D, Baum L, Becker F, Berkovic SF, W, Eggert KM, Albanese A, Del Sorbo F, Tolosa E, Bradfield JP, Brody LC, Buono RJ, Catarino CB, Cardozo A, Deuschl G, Hellriegel H, Klockgether T, Cavalleri GL, Cherny SS, Chinthapalli K, Coffey AJ, Dodel R, Sampaio C, Coelho M, Djaldetti R, Melamed Compston A, Cossette P, de Haan GJ, De Jonghe P, E, Gasser T, Kamm C, Meco G, Colosimo C, Rascol O, de Kovel CGF, Delanty N, Depondt C, Dlugos DJ, Meissner WG, Tison F, Poewe W; European Multiple Doherty CP, Elger CE, Ferraro TN, Feucht M, Franke System Atrophy Study Group (2013) The natural A, French J, Gaus V, Goldstein DB, Gui H, Guo Y, history of multiple system atrophy: a prospective Hakonarson H, Hallmann H, Heinzen EL, Helbig I, European cohort study. Lancet Neurol 12(3):264-74 Hjalgrim H, Jackson M, Jamnadas-Khoda J, Janz D, Johnson MR, Kälviäinen R, Kantanen AM, Roettger Y, Du Y, Bacher M, Zerr I, Dodel R, Bach JP Kasperavičiūte D, Kasteleijn-Nolst Trenite D, (2013) Immunotherapy in prion disease. Nat Rev Koeleman BPC, Kunz WS, Kwan P, Lau YL, Lehesjoki Neurol 9(2):98-105 A-L, Lerche H, Leu C, Lieb W, Lindhout D, Lo W, Lowenstein DH, Malovini A, Marson AG, McCormack Eggert K, Öhlwein C, Kassubek J, Wolz M, Kupsch A, M, Mills JL, Moerzinger M, Møller RS, Molloy AM. Ceballos-Baumann A, Ehret R, Polzer U, Klostermann Muhle H, Newton M, Ng P-W, Nöthen MN, Nürnberg F, Schwarz J, Fuchs G, Jost W, Albert A, Haag A, P, O’Brien TJ, Oliver KL, Palotie A, Pangilinan F, Hermsen A, Lohmüller K, Kuhn K, Wangemann M, Pernhorst K, Petrovski S, Privitera M, Radtke R, Reif Oertel WH; In Cooperation With the German PS, Rosenow F, Ruppert A-K, Sander T, Scattergood Competence Network on Parkinson’s Disease (2014) T, Schachter S, Schankin C, Scheffer IE, Schmitz B, Influence of the nonergot dopamine agonist piribedil Schoch S, Sham PC, Sisodiya S, Smith DF, Smith PE, on vigilance in patients With Parkinson Disease and Speed D, Sperling MR, Steffens M, Stephani U, excessive daytime sleepiness (PiViCog-PD): an 11- Striano P, Stroink H, Surges R, Tan KM, The KORA week randomized comparison trial against study group, Thomas GN, Todaro M, Tostevin A, pramipexole and ropinirole. Clin Neuropharmacol 37: Tozzi R, Trucks H, Visscher F, von Spiczak S, Walley 116-22 NM, Weber YG, Wei Z, Whelan C, Yang W, Zara F, Zimprich F. (2014) Genetic determinants of common Sanchez-Padilla J, Guzman JN, Ilijic E, Kondapalli J, epilepsies: a meta-analysis of genome-wide Galtieri DJ, Yang B, Schieber S, Oertel W, Wokosin D, association studies. Lancet Neurology 13(9):893-903 Schumacker P, Surmeier DJ (2014) Mitochondrial oxidant stress in locus coeruleus is regulated by Kallenberg K, Goldmann T, Menke J, Strik H, Bock activity and nitric oxide synthase. Nat Neurosci 2014; HC, Stockhammer F, Buhk JH, Frahm J, Dechent P, 17(6): 832-840 Knauth M (2013) Glioma infiltration of the corpus callosum: early signs detected by DTI J Neurooncol Schuepbach WMM, Rau J, Knudsen K, Volkmann J, 112(2):217-22 Krack P, Timmermann L, Hälbig TD, Hesekamp H, Navarro SM, Meier N, Falk D, Mehdorn M, Paschen Huber M, Heink S, Pagenstecher A, Reinhard K, Ritter S, Maarouf M, Barbe MT, Fink GR, Kupsch A, Gruber J, Visekruna A, Guralnik A, Bollig N, Jeltsch K, D, Schneider G-H, Krack P, Seigneuret E, Kistner A, Heinemann C, Wittmann E, Buch T, Prazeres da Chaynes P, Ory-Magne F, Brefel Courbon C, Vesper J, Costa O, Brüstle A, Brenner D, Mak TW, Mittrücker Schnitzler A, Wojtecki L, Houeto J-L, Bataille B, HW, Tackenberg B, Kamradt T, Lohoff M (2013) Maltete D, Damier P, Raoul S, Sixel-Döring F, Hellwig Pathogenic IL-17A dependent help of Tc17 cells for D, Gharabaghi A, Krüger R, Pinsker MO, Amtage F, Th17-mediated autoimmune encephalomyelitis. J Regis J-M, Witjas T, Thobois S, Mertens P, Kloss M, Clin Invest 123: 247-260. Hartmann A, Oertel WH, Post B, Speelman H, Agid Y, Schade-Brittinger C, Deuschl G, for the EARLYSTIM Study Group. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Contact Details: Med 2013; 368: 610-622 Baldingerstraße, 35043 Marburg Tel.:++49 (0) 6421-58 66299 Chiu WH, Carlsson T, Depboylu C, Höglinger GU, Director: Professor Dr. Richard Dodel Oertel WH, Ries V (2014) Selegiline normalizes, while l-DOPA sustains the increased number of dopamine neurons in the olfactory bulb in a 6-OHDA mouse model of Parkinson's disease. Neuropharmacology 79:212-21.
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Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Chair Professor K. Becker Emotion recognition deficits were examined in a Professor H. Remschmidt (Emeritus), large sample of children and adolescents with autism spectrum disorders and other psychiatric disorders. Professor I. Kamp-Becker (W2 . since 2014) A short questionnaire with few interview questions for screening of ASD was developed. The Main fields of research effectiveness of the Parenting Program „Stepping Research in child and adolescent psychiatry and Stones/Triple P“ for children diagnosed with autism (neuro)developmental psychopathology, basic spectrum disorder was evaluated. research in neuropsychology, therapy, and genetics in autism spectrum disorders and ADHD and Title Neurobiological principles of social emotions comorbid conditions; fMRI studies; therapy Principal investigators S. Krach, I. Kamp-Becker, S. evaluation, early childhood research, research in Knake (Dept. of Neurology), W. Einhaeuser-Treyer eating disorders (obesity, anorexia nervosa), (Working Group Neurophysics) & A. Jansen (Working transcranial direct current stimulation (tDCS), gene- Group Brain Imaging) environment interaction, longitudinal research, Summary The multimodal project evaluates basic psychopharmacoepidemiology, health economics, and clinical aspects of development, processing as medical education. well as regulation of social emotions. In addition to the selection of research projects Funded by Philipps-University Marburg (Research listed below, we are part of the German anorexia- Promotion Fund) register study initiated in 2014 (PI B. Herpertz- Funding period 2012 – 2014 Dahlmann, Aachen; local PI’s K. Becker, J. Pfeiffer) and involved in different groups drawing up or Title The female variant of Asperger’s syndrome revising medical guidelines in the field of child and Principal investigators Kamp-Becker, L. Paye, S. adolescent psychiatry (e.g. suicidality, non-suicidal Fraessle, L. Rademacher, C. Kauschke (Institute for self-injurious behavior, autism, conduct disorder). Linguistics, Marburg) & K. Becker Summary The research project investigates the Research projects characteristics of female individuals with Asperger’s Research group Autism Spectrum Disorders Syndrome or a high-functioning autism spectrum Title Search and analyses of candidate genes for disorder. Complex social emotions (“social pain”), autism spectrum disorders especially for high- communicative and narrative skills, as well as the functioning autism spectrum disorders ability to verbalize internal conditions (“Internal Principal investigators A. K. Wermter, I. Kamp- State Language”) are analyzed in female children and Becker & K. Becker adolescents with autistic disorders. Both the Summary This project aims at the identification of neuronal correlates of social emotions and their candidate genes and genetic variants, influencing verbalization on a behavioural level are examined. particular core symptoms of the autism spectrum Funded by Philipps University Marburg disorders (ASD). The analyses were performed in a sample of individuals with high-functioning ASD Title Empathy, Autism and Oxytocin – an (Asperger syndrome, high-functioning autism, and investigation by means of functional magnetic atypical autism) and their parents. Under resonance imaging and moleculargenetic analyses consideration of the hypothesis that the mental Principal investigators A.-K. Wermter, I. Kamp- retardation of the majority of patients with autism Becker & S. Krach considerably hampers the detection of candidate Summary This project aimed for the first time at genes for ASD, the investigated sample of individuals investigating the ability for empathy in adolescents with high-functioning ASD has a potential to with high-functioning ASD in a wide battery of elucidate genes underlying the susceptibility to ASD. paradigms using fMRT and analyzing the modulating effect of intranasal oxytocin. Additionally, the Title Etiological, diagnostic, differential diagnoses influence of the SNP rs53576 in the oxytocin and therapeutic aspects of autism spectrum disorder receptor gene (OXTR) on the empathy and the Principal investigators I. Kamp-Becker & K. Becker activation pattern in the neural network of empathy Summary This project aims at the investigation of should be investigated. genetic, neuronal, diagnostic as well as differential Funded by DFG (WE5076/1-1) – German Research diagnostic aspects of autism spectrum disorders. Foundation
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Funding period 2014 – 2016 part of compulsory medical training. CAP is either taught in independent lectures or integrated in Title Scientific Accompanying Study ADHD Care lectures on psychiatry, pediatrics and/or Concept (Wissenschaftliche Begleitevaluationsstudie psychosomatics. CAP is often taught for students of zum BKK-Versorgungskonzept ADHS) other disciplines as well, e.g. psychology or education. Principal investigators K. John, F. Mattejat & K.
Becker Title Medical education in child & adolescent Summary The study analyzed the effectiveness of psychiatry the newly established outpatient treatment care Principal investigator C. Bachmann & T. Lempp (CAP, concept “ADHD” for ADHD-patients between the University of Frankfurt) ages of 4 and 17 insured by BKK insurance funds in Summary It is unclear, whether the current German Baden-Wuerttemberg in comparison to Treatment child and adolescent psychiatry (CAP) medical school as Usual. curriculum is helpful for future primary care doctors Funded by German Federal Ministry of Health regarding evaluation and management of children Funding period 2010 – 2013 and adolescents with mental health problems. To address this question, 500 GPs and 348 pediatricians Health economics were surveyed, asking them to rate the relevance of Title Psychopharmacoepidemiology in child & CAP-related skills and knowledge for their daily adolescent psychiatry practice. Principal investigators C. Bachmann & F. Hoffmann Funded by Excellence-in-teaching award (Goethe- (University Bremen) University Frankfurt) and research grant from Summary This project aims to analyze the Actelion Pharmaceuticals prescription of psychotropic substances for children Funding period 2014 and adolescents in Germany, mainly based on secondary data from health insurance funds (e.g. BARMER GEK, AOK). So far, several articles on Research Group Developmental Psychopathology utilization of antidepressants and antipsychotics and Title Neuropsychological basic deficits and on outpatient treatment (Pharmacotherapy and/or developmental pathways in children at risk of psychotherapy) of children and adolescents with developing attentiondeficit-/hyperactivity disorder ADHD, tic disorders, eating disorders and depression (ADHD) – The AUFMERKSAM Longitudinal Study have been published. Principal investigators K. Becker, U. Pauli-Pott Summary Inhibitory control and delay aversion have Title Health economics of conduct disorder been supposed to underlie the complex ADHD Principal investigators C. Bachmann symptoms, to be involved in their developmental Summary Patients with conduct disorder constitute trajectories, and, thereby, to moderate the effects of a large portion of child and adolescent psychiatric environmental risk factors. Empirical research on inpatients and outpatients. For Germany, to date these issues is scant. We conduct a longitudinal there is almost no data on health services utilization study on the putative basic deficit-environment of this group and the resulting economic interactions involving 210 preschoolers (70% thereof consequences. Based on health insurance data (AOK at an increased risk of developing ADHD). Nordost), our research evaluates health insurance Funded by DFG – German Research Foundation expenses for these patients, also considering Funding period 2012 – 2015 regional and socio-economic influencing factors. Title Attentiondeficit-/hyperactivity (ADHD) symptoms, eating behaviors, and body weight at age Teaching/Research projects 6 Title Teaching child and adolescent psychiatry in Principal investigators U. Pauli-Pott & K. Becker German medical schools Summary Overweight and obesity represent serious, Principal investigators K. Becker health threatening conditions that are prevalent Summary The current scope of teaching in the field already in early school-age. In this project we of child and adolescent psychiatry (CAP) in German analyze the associations between early medical schools was investigated. All chairs of child psychopathological symptoms, impulsive eating, and adolescent psychiatry were asked to provide physical activity, and body weight in children at detailed information on involvement in compulsory primary school enrollment. The study is conducted in and non-compulsory medical training, scope of cooperation with the Health Department of the lectures in CAP and courses for students of other Marburg-Biedenkopf district (Fachbereich disciplines. In 25 out of 26 medical schools with a Gesundheit des Landkreises Marburg-Biedenkopf, chair for CAP, the medical specialty of CAP is already Dr. B. Wollenberg, A. Schroer)
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Title Psychiatric disorders in preschool years emotionality precedes psychotic episodes, we do not Principal investigators I. Kamp-Becker & K. Becker know why individuals fail to regulate these emotions Summary There is increasing awareness in the field effectively. The project aims to identify difficulties in of child and adolescent psychiatry of the existence of emotion regulation (ER) that constitute the unknown psychiatric disorders in preschool-aged children. This links between stressors, negative emotions, and research projects aims to evaluate diagnostic as well psychotic symptoms in persons at risk of developing as therapeutic options in this age range. A a first psychotic episode or relapse. The project standardized observation method for parent-child involves testing the effect of different ER-strategies interaction will be developed and evaluated. on emotions, psycho-physiological reactions and symptoms. In addition, functional magnetic resonance imaging (fMRI) is employed to test Research group Social Neuroscience whether difficulties in down-regulating distressing Main fields of research emotions are associated with stronger activations of Social emotions in autism spectrum disorders; neural cortico-limbic structures including PFC and correlates and multimodal data integration in social amygdala. neuroscience of neuropsychiatric conditions; Funded by German Research Foundation (DFG) We use fMRI, pupillometry, eyetracking, personality Funding period 2013 – 2016 and behavior observation to disentangle the neural architecture of (dys)functional processes of social Other Research Projects interaction in clinical samples (autism) and healthy Title Transcranial direct current stimulation (tDCS) – controls. a possible new treatment option in child and
adolescent attention deficit /hyperactivity disorder Title Social interaction with human robots in (ADHD) Asperger syndrome Principal investigators A. Sotnikova, C. Soff, K. Principal investigator S. Krach & I. Kamp-Becker Becker, M. Siniatchkin (Kiel) Summary In cooperation with Bielefeld University Summary ADHD is characterized by an (faculty of technology, faculty of linguistic) vision underactivation of the neuronal networks playing a behaviour and dilatations of pupils during role in the regulation of attention, executive interaction with human robots were examined in functions and control of impulsivity. The dorsolateral patients with Asperger syndrome. prefrontal cortex is one of the main components of Funded by DFG – German Research Foundation these networks. This study aimed to investigate a Funding period 2010 – 2013 possible therapeutic influence of the anodal tDCS on
the dorsolateral prefrontal cortex in order to restore Title Neural foundations, plasticity and regulation of the deficient neuronal activation by means of a non- embarrassment in social anxiety invasive brain stimulation. Principal investigators S. Krach, B. Hanewald, S. Funded by UKGM – University Hospital Giessen and Westermann & F. Paulus Marburg Summary Social phobia ranges among the most Funding period 2011 – 2013 often diagnosed psychiatric conditions (life-time prevalence of 8-10%). The fear of public failure and Title Non suicidal self-injury with regard to resilience accordingly to overtly get stuck into embarrassing in a school sample. situations can be such strong that people with social Principal investigator(s) A. Thum, J. Pfeiffer & K. phobia entirely avoid social interactions. In the Becker context of neuroscientific studies the social emotion Summary Aim of this survey is to investigate the of embarrassment and its underlying neural relationship between non-suicidal self-injury and foundations have not been studied so far. In the resilience in adolescents. A school sample of more present project we investigate the multimodal than 500 ninth graders of different schools and dynamics of the embarrassment experience and try schooltypes (Haupt-/Realschule as well as to disentangle how this process is affected in Gymnasium) of Marburg-Biedenkopf district were (subclinical) patients with social anxiety. investigated. They were asked inter alia for self-harm Funded by BR-Stiftung behaviour (using as instruments the Self-Harm- Funding period 2012 – 2015 Behavior-Questionnaire and the modified Title Emotion regulation and its neural correlates in Ottawa/Ulm Self-Harm Inventory MOUSI), as well as the process of transition to psychosis for depressive symptoms (Allgemeine Depressions- Principal investigators T. Lincoln (Hamburg), S. Krach skala ADS), drug use and resilience (German & A. Jansen (Psychology, Marburg) translation of the Resilience Scale, RS-25). First Summary The processes underlying transition into a results show that 23% of the investigated first psychotic episode or relapse are not yet well adolescents reported self-harm behavior at least understood. Although a state of heightened
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Clinical Institutions once in the past, 10% had shown self-harm behavior Most important publications four times or more. Mean age of starting self-harm Pauli-Pott U, Roller A, Heinzel-Gutenbrunner M, was about 13 years. Male adolescents started at an Mingebach T, Dalir S, Becker, K (2014) Inhibitory earlier age, whereas girls showed increased control and delay aversion in unaffected incidence of self-harm. There is a positive correlation preschoolers with a positive family history of of depressive symptoms and self-harm behavior. attention deficit hyperactivity disorder. Journal of Child Psychology and Psychiatry, 55: 1117-1124 Title Psychosocial Development of Adolescents with Hearing Impairment Pauli-Pott U, Dalir S, Mingebach T, Roller A, Becker Principal Investigators M. Pinquart (Psychology, K (2013) Do different ADHD-related etiological risks Marburg) & J. Pfeiffer involve specific neuropsychological pathways? An Summary We examined psychosocial development analysis of mediation processes by inhibitory control (developmental tasks, alcohol consumption, bullying, and delay aversion. Journal of Child Psychology and and psychological problems) of adolescents with Psychiatry 54:800-809 hearing impairment in comparison to adolescents without HI. The studies assessed 181 adolescents Sprenger L, Bühler E, Poustka L, Bach C, Heinzel- from schools for students with HI and 259 hearing Gutenbrunner M, Kamp-Becker I, Bachmann C peers from regular schools. It is concluded that (2013) Impact of ADHD symptoms on Autism adolescents with acquired deafness are in a Spectrum Disorder Symptom Severity. Research in particular need for reducing emotional and Developmental Disabilities 34:3545–3552 behavioral problems. Bachmann C, Manthey T, Kamp-Becker I, Glaeske G, Title Psychosocial Development of Adolescents from Hoffmann F (2013) Psychopharmacological Boarding Schools treatment in children and adolescents with autism Principal Investigators J. Pfeiffer & M. Pinquart spectrum disorders in Germany. Research in (Psychology, Marburg) Developmental Disabilities 34:2551–2563 Summary Adolescents who attend boarding schools share more time with peers than students from John K, Becker K, Mattejat F (2013) Impact of family- regular schools. This might lead to a different oriented rehabilitation and prevention: An inpatient development (own behaviour, socialization). program for mothers with breast cancer and their Therefore, we examined the development of 706 children. Psycho-Oncology, 22:2684-2692 German adolescents at boarding and regular schools in a cross-sectional design. We conclude that anti- Pinquart M, Pfeiffer JP (2014) Change in bullying-interventions are needed to help boarding psychological problems of adolescents with and schools. without visual impairment. European Child and Adolescent Psychiatry, 23, 571–578 Title Violent crime perpetrated by young people – results of a 13-year longitudinal study Nikitopoulos J, Zohsel K, Blomeyer D, Buchmann AF, Principal investigator H. Remschmidt Schmid B, Jennen-Steinmetz C, Becker K, Schmidt Summary 114 offenders (103 male, 11 female), MH, Esser G, Brandeis D, Banaschewski T, Laucht M whose age at the time of the offense was 17.6 ± 1.9 (2014) Are infants differentially sensitive to years (mean, standard deviation) were investigated. parenting? Early maternal care, DRD4 genotype and They underwent assessment in an overall period of externalizing behavior during adolescence. Journal of nearly 31 years after taking the lives of 70 persons. Psychiatric Research 59:53-59 In 96 cases (84.2%), a psychiatric diagnosis was made at the time of assessment; this was not the Schulte-Rüther M, Greimel E, Piefke M, Kamp- case for only 18 individuals (15.8%), 20 (17.5%) were Becker I, Remschmidt H, Fink GR, Herpertz- admitted to a psychiatric hospital or drug withdrawal Dahlmann B, Konrad K (2014). Age-dependent clinic. 44 (38.6%) developed into chronic criminal changes in the neural substrates of empathy in offenders who continued to commit crimes after the autism spectrum disorder. Social Cognitive and index offense. Affective Neuroscience 9:1118-1126 Funded by Scientific Association for Child and Adolescence Psychiatry (Berlin) Funding period 2008 – 2013 Contact Details: Hans-Sachs-Str. 6, 35039 Marburg Phone:++49 (0) 6421-58 66471 General information about the institute Director: Professor Dr. Katja Becker
Research funding 419.221,03 €
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Department of Psychiatry and Psychotherapy
Chair Professor T. Kircher phenomena, language, social and cultural behaviour, Professor Dr. Dr. U. Dannlowski, Professor Dr. A. expectations and motivational states relate to Jansen, Professor Dr. C. Konrad specific neural networks in the brain. Focus of research: Main fields of research Schizophrenia, affective disorders, anxiety Research group Prof. Dr. Dr. Dannlowski disorders Imaging in Psychiatry Neuroimaging The section „Imaging in Psychiatry“ investigates the Genetic imaging neurobiology of emotions and affective disorders by Neurobiology of Psychotherapy using multimodal neuroimaging techniques. Affective disorders, i.e. major depressive disorder Research group Prof. Dr. Konrad and bipolar disorder, are complex and Cognitive Neuropsychiatry heterogeneous phenotypes with genetic and The main focus of the research group is the environmental risk factors interacting in their exploration of the neurobiology of affective etiology. The neurobiological mechanisms by which disorders as well as mechanisms of therapy in these risk factors exert their detrimental influence affective disorders. Emotional and cognitive brain- on brain structure and function are poorly functions are investigated. As methods of brain- understood. The aims of the section “imaging in imaging, functional and structural MRI as well as psychiatry” are to integrate clinical and electroencephalography (EEG) are applied. The neurobiological determinants of interacting genetic anatomy and function of the human brain, especially and environmental risk factors involved in the hippocampus, and genetic influences on the etiology, onset and the course of affective disorders. cognitive functions and brain structures are areas of special interest. Psychotherapy such as CBASP for Research group Prof. Dr. Jansen chronic depression and CBT for anxiety orders are Multimodal Imaging in Cognitive Neuroscience explored in large national cooperations. One of the primary research goals is to understand the basic principles underlying hemispheric Core-Unit Brainimaging Prof. Dr. Jansen lateralization. This question is addressed using The Core-Unit Brainimaging is a core resource that multimodal imaging techniques, in particular offers technical and administrative assistance to magnetic resonance imaging, aiming at permit scientists of the University Marburg and their characterizing the principles of hemispheric collaborators to conduct human brain imaging lateralization in terms of asymmetries in brain research. This will be accomplished by offering connectivity. In the research team, there are further access to state of the art imaging technology, developed methods to improve the quality of the infrastructure, and personnel assistance. We use data acquisition, to assess the reliability of imaging various magnetic resonance imaging methods, data, to integrate different imaging modalities, and including functional and structural magnetic to advance data analysis techniques. These methods resonance imaging, diffusion tensor imaging and are applied in various research projects in cognitive magnetic resonance spectroscopy. Our highly and clinical neuroscience, for instance in the field of experienced team is composed of physicists, imaging genetics and in multicenter studies on computer scientists, and radiographers. The psychiatric disorders. laboratory is equipped with a 3 T Siemens scanner, two EEG systems and various MR compatible eye- tracker systems. Research group Prof. Dr. Kircher Systems Neuroscience Research projects Systems neuroscience encompasses molecular and Title Language in the predictive brain: Using cognitive neuroscience. Its goal is to further our naturalistic stimuli to assess forward models of understanding of the relationship between cognitive language processing and their neural phenomena and the physical matter of the brain. implementation Using a combination of genetics, behavioral testing, Principal investigator(s) I. Bornkessel-Schlesewsky, and advanced brain imaging, our cognitive T. Kircher& R. Wiese neuroscience research endeavors seek to elucidate Summary Prediction has been termed a possible how high-level functions, such as psychopathological unifying concept of brain function. It is also
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Clinical Institutions pervasive in language, where upcoming input is Funded period 2009 – 2013 anticipated at various levels (from sound to discourse). By using fMRI to examine several of these Title Neural correlates of human-robot levels of prediction in naturalistic stories, this project communication aims to illuminate possible unified neural bases for Principal investigator(s) S. Krach, I. Kamp-Becker, B. prediction in language and beyond. Wrede & A. Jansen Funded by Philipps-University of Marburg (ExIn- Summary Aim of the project is to investigate healthy Sondermittel) subjects and persons with the diagnosis of Autism Funding period 2012 – 2015 Spectrum Disorders (ASD) with regard to their ability to take the perspective of another person or Title High Paternal Age as a Risk Factor for Social humanoid robot, respectively. Therefore N = 15 Deficits in Neuropsychiatric Disorders: Genes, Brain persons with the diagnosis of ASD will be examined and Behavior - A Translational Approach by means of functional MRI, eyetracking and Principal investigator(s) R.K.W. Schwarting, T. optotracking techniques. Forms of perspective- Kircher, A. Krug, & M. Wöhr taking will be investigated by addressing the Summary High paternal age is a risk factor for participants' ability to empathically feel pain of neurodevelopmental disorders such as others, experience vicarious embarrassment and to schizophrenia. Using a rat model, effects of high maintain joint attention. These parameters will be paternal age on behaviors with relevance to correlated with individual differences in personality schizophrenia-related social deficits and associated traits. First results of the current study are expected candidate genes will be examined. Such candidate in spring 2012. genes will then be used for the characterization of Funding by DFG – German Research Foundation genotype-dependent differences in brain activation Funded period 2010 – 2013 during social tasks in healthy human subjects. Funded by Philipps-University of Marburg (ExIn- Title Correlative imaging of molecular-genetic risk Sondermittel) variants for schizophrenia and bipolar disorder Funding period 3 years Principal investigator(s) A. Krug, T. Kircher & M. Rietschel Title Verbundprojekt: Verbund Psychotherapie Panik Summary In this project, effects of genetic variation, BMBF multi-center project: Psychotherapy in panic environmental effects as well as their interactions on disorder brain activation and brain structure are investigated Principal investigator(s) T. Kircher in patients with schizophrenia, bipolar disorder and Summary In context of the clinical multi-center healthy controls. Project, funded by the German Federal Ministry of Funded by DFG – German Research Foundation Education and Research, fMRI data of patients with Funding period 2010 – 2015 panic disorder are acquired before and after cognitive behavioural therapy (CBT). Three different Title The neural correlates of natural social- paradigms have been implemented: Semantic, communicative perception in healthy subjects and interoceptive and subliminal priming. We expect patients with schizophrenia: Comprehension, that the construction of new, not anxiety-related detection and interpretation of verbal and non- neural networks is an important component of CBT. verbal information Funded by: BMBF – Federal Ministry of Education Principal investigator(s) T. Kircher & B. Straube and Research Summary Patients with schizophrenia show Funded period: 2006 – 2013 dysfunctional communication skills. The DFG- founded fMRI-project is focussed on three important Title Core Facility for neuro-scientific research levels of natural social communication: (1) The Principal investigator(s) T. Kircher, W. Oertel & G. comprehension of non-verbal information, (2) the Heverhagen detection of social-affective content and (3) the Summary Neuroscientific research for MRI is interpretation of social cues. Beside the general provided and administrated by a core facility at the difficulties for patients with schizophrenia, we Dept. of Psychiatry and Psychotherapy. The core expect symptom specific dysfunctions in the three facility is responsible for scan time allocation as well different experimental tasks. as for the maintaining of technical equipment and Funded by DFG – German Science Foundation know-how that is needed for planning, executing Funded period 2010 – 2015 and evaluating neuropsychological experiments in the MRI. In this project, a position for a computer Title Functional and structural connectivity of scientist is funded for 3 years. patients with schizophrenia Funded by von Behring-Röntgen Foundation Principal investigator(s) T. Kircher & A. Jansen
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Summary The causes of schizophrenia have been the function and risk of depressive relapse in MDD. subject of much debate. One prominent hypothesis Funded by UKGM – University Medical Centre is that alterations in both structural and functional Giessen and Marburg brain connectivity are responsible for various Funded period 2012 – 2014 symptoms associated with schizophrenia. In the present project we use structural and functional MR- T Title Genetic variants and risk of brain structure as techniques to investigate alterations of brain predictors of treatment success in recurrent connectivity patterns in specific subgroups of depressive disorders patients with schizophrenia. Principal investigator(s) A. Krug & C. Konrad Funded b: DFG – German Research Foundation Summary In this project, genetic variation as well as Funded period 2011 – 2015 brain structure in patients with major depression is investigated. The main purpose of the study is to Title Effects of meditation on functional and estimate the predictive value of these variables on structural connectivity of the brain: A combined therapy outcome and maintenance of therapeutic fMRI and DTI study effects. Principal investigator(s) A. Jansen, J. Sommer, D. Funded by UKGM – University Medical Centre Laneri, U. Ott & B. Hölzel Giessen and Marburg Summary Little is currently known about the Funded period 2010 – 2014 cerebral characteristics that underlie the complex processes of meditation. The present project Title Delusions and hallucinations in patients with combines for the first time both functional and schizophrenia: is cognitive behavioural therapy structural MR techniques to determine (CBTp) or acceptance-oriented therapy (ACT) more simultaneously whether the practice of meditation effective in reducing positive symptoms in patients produces structural changes in the white matter with schizophrenia? and/or in the functional network connectivity at rest. Principal investigator(s) S. Mehl & D. Leube The combined results of these two approaches will Summary 80 patients with schizophrenia are show which regions of the brain are involved in included in a randomized controlled trial in order to meditation. compare the effectiveness of traditional cognitive Funded by von Behring-Röntgen Foundation behavioural therapy (CBTp) and acceptance-oriented Funded period 2012 – 2014 therapy (ACT) in order to reduce delusions and hallucinations. First, patients psychopathological Title Neural correlates of reward anticipation in symptoms are assessed, then patients are patients with Major Depression: Pathophysiological randomized and receive either 20 individual sessions relevance and therapeutic implications of CBT or ACT and are examined, again. Principal investigator(s) I. Falkenberg, S. Krach, A. Funded by UKGM – University Medical Centre Nagels & T. Kircher Giessen and Marburg Summary Anhedonia is a prominent feature of Funded period 2012 – 2015 Major Depressive Disorder (MDD). Previous research suggests that anhedonia may be the Title Emotion Regulation and its Neural Correlates in endophenotype of a dysfunctional mesolimbic the Process of Transition to Psychosis dopaminergic reward system. The aim of this project Principal investigator(s) S. Krach, T. Lincoln, A. is to promote the patients hedonic abilities by means Jansen & S. Westermann of a specific training using humor related techniques Summary In this project we have finished the and to characterize the effects of such training on process of fMRI paradigm development and already the neural correlates of reward processing in MDD. successfully piloted the experiments in N = 10 Funded by von Behring-Röntgen Foundation healthy control participants. We applied two fMRI Funded period 2011 – 2014 experiments, one on the regulation of basic emotions such as fear and a second one to study the Title Innovative psychotherapy techniques in the regulation of social emotions, here social exclusion. maintenance therapy of Major Depression In a next step we will include patients with a Principal investigator(s) I. Falkenberg & A. Nagels diagnosis of schizophrenia in the study protocol. Summary Major Depressive Disorder (MDD) is Funded by DFG – German Research Foundation associated with reduced stress tolerance and Funded period: 2012 – 2015 dysfunction of the HPA axis. The latter is related to an increased risk of depressive relapse. The aim of Title Simultaneous measurement of EEG and fMRI: this study is to test the influence of a training of establishing the methodology for testing the humor related abilities on stress tolerance, HPA
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Clinical Institutions
‘dysconnectivity hypothesis’ in patients with Funded period 2011 – 2014 schizophrenia Principal investigator(s) B. Straube, G. Sammer & H. Title Ultra-early relapse detection in schizophrenia: a Gebhardt modern approach using ecological momentary Summary Patients with schizophrenia show assessment and dynamic system modeling dysfunctional integration of information from Principal investigator(s) S. Westermann, A. Jansen different sensory channels. It has been hypothesized & S. Krach that this dysfunction is a result of dysconnectivity Summary The successful development and setup of between disparate brain regions. To test this the technical infrastructure (ecological momentary “dysconnectivity hypothesis” with temporal and assessment, text messaging webservice, etc.) was spatial accuracy the project focuses on establishing followed by a pilot study with N=31 healthy the methodology for simultaneous measurement of participants, which revealed associations between EEG and fMRI in healthy subjects and patients with the dynamics of emotionality and non-clinical schizophrenia. positive symptoms. Currently, the main pilot study Funded by von Behring-Röntgen Foundation with patients with a diagnosis of schizophrenia is Funded period 2012 – 2015 underway. Funded by UKGM – University Medical Centre Title Neural foundations, plasticity, and regulation of Giessen and Marburg embarrassment in social anxiety Funding period 2013 – 2015 Principal investigator(s) D. Krach, B. Hanewald, S. Westermann & F. Paulus Title Imaging Epigenetics - Assoziation Summary In this project we develop and apply an epigenetischer Marker mit limbischer Responsivität fMRI paradigm to induce first-person feelings of auf aversive Stimuli embarrassment in a social interaction with other Principal investigator(s) U. Dannlowski participants. In a second step we will investigate Summary The study aims at investigating the persons with social anxiety with this paradigm. neurobiological underpinnings of DNA methylation Funded by von Behring-Röntgen Foundation at the 5-HTT and BDNF gene in a healthy human Funded period 2012 – 2015 sample using functional and structural MRI. First results show a strong association of methylation Title Neural mechanisms and predictors of affect rates at the 5-HTT gene and hippocampal volumes. regulation improvement induced by psychotherapy The data suggest that epigenetic processes alter Principal investigator(s) C. Konrad (Marburg), K. brain structure with relevance to psychiatric Schnell (Heidelberg) & H. Walter (Berlin) disorders such as major depression. Summary Patients undergoing two forms of Funded by UKGM – University Medical Centre psychotherapy for chronic depression (CBASP vs. Giessen and Marburg supportive psychotherapy) are examined by MRI Funding period 2013 – 2015 before and after therapy using paradigms reflecting unspecific, symptom-related changes and specifically Title Longitudinal study on brain structure and targeted by CBASP. The hypotheses are tested that function in patients with major depression and both groups show unspecific, symptom related healthy subjects changes in the first paradigms, while changes in Principal investigator(s) A. Krug & C. Konrad specific paradigms will be significantly larger under Summary Within this project, a sample of healthy CBASP-treatment. subjects and patients with major depression is to be Funded by DFG – German Research Foundation re-investigated three years after initial investigation. Funded period 2010 – 2013 All subjects are being scanned with structural and functional MRI and these measures will be Title Group intervention to improve stigmatization- correlated with course of illness, genetic and management competence and empowerment in environmental risk factors. In 2014, 71 subjects were psychiatric disease (STEM) re-investigated. Principal investigator(s) C. Konrad (Marburg) & W. Funded by von Behring-Röntgen Foundation Gaebel (Düsseldorf) Funding period 2014 – 2017 Summary A group psychotherapy to improve quality of life and empowerment , to manage disease Title The dysconnectivity hypothesis of stigmatization and reduce self-stigmatization is schizophrenia: Determination of test-retest tested in a multicenter setting, including 512 reliability of fMRI paradigms patients from 24 institutions. Principal investigator(s) A. Jansen & S. Westermann Funded by BMBF – Federal Ministry of Education Summary Functional imaging paradigms that are and Research used in clinical cohorts should yield robust activation
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Clinical Institutions and tap into cognitive and affective processes that for the perception of the multisensory consequences are important for the understanding of the clinical of one’s own actions. 1) supramodal vs. unimodal disorder. A further important aspect, in particular effects of action-sensory feedback matching with regard to the longitudinal aspect of the study processing, 2) the neural correlates of supramodal design, is the reliability of brain activation measures. predictive mechanisms and their consequences and, In the present project, we aim to further understand 3) predictive mechanisms during tool-use actions how the reliability of fMRI imaging markers can be and the perception of related multisensory improved. consequences. Funded by Else Kröner-Fresenius Foundation Funded by DFG SFB/TR 135 TP A3 – German Funding period 2013 – 2016 Research Foundation, Transregional Collaborative Research Centre Title Neural processes of social interaction in people Funding period 2014 – 2017 with genetic and environmental risk factors for schizophrenia Title International Research Training Group (IRTG) Principal investigator(s) T. Kircher & B. Straube “The Brain in Action” Summary Social categorization mediates behaviour Principal investigator(s): T. Kircher during interpersonal interaction. The neural Summary This project is focused on the neural processes and the interaction of these systems and processes that underlie perception and environmental factors with genetic risk for action in everyday living. Especially predictive schizophrenia has not yet been explored. In this mechanisms for the multisensory perception of project the influence of environmental (immigration action consequences as well as multisensory status) and genetic risk factors (relatives of patients integration processes are investigated to understand with schizophrenia) for schizophrenia on neural how we perceive and adequately interact with the mirror neuron and Theory of Mind (ToM) networks world. will be investigated. Funded by DFG (GRK 1901/1) – German Funded by DFG (KI588 16-1) – German Research ResearchFoundation Foundation Funding period 2013 – 2018 Funding period 2014 – 2017 Title Science and Development Contract Title Neural processes of social interaction in people Principal investigator(s) T. Kircher with genetic and environmental risk factors for Summary Variations in specific genetic schizophrenia polymorphisms might contribute to Principal investigator(s): B. Straube, T. Kircher neurophysiological differences and therapeutic Summary: Social categorization mediates behaviour outcomes within subgroups of patients with panic during interpersonal interaction. The neural disorder and agoraphobia. Here, we test this processes and the interaction of these hypothesis by combining genetic with behavioural environmental factors with genetic risk for techniques and neuroimaging in a clinical schizophrenia has not yet been explored. In this multicentre trial, where patients receive 12 sessions project the influence of environmental (immigration of manualized cognitive-behavioural therapy and status) and genetic risk factors (relatives of patients were genotyped for specific candidate gens. with schizophrenia) for schizophrenia on neural Funded by BMBF mirror neuron and Theory of Mind (ToM) networks Funding period 2013 – 2014 will be investigated. Funded by DFG (STR 1146/4-1) – German Research Title Social Networks and the Brain Foundation Principal investigator(s) J. Sommer & P. Kenning Funding period 2014 – 2017 Summary Social Network Sites (SNS) play a major role in modern technology-bounded societies. Title Intermodal integration of perception of one`s Fostering connectivity in SNS is essential for own actions – Cardinal mechanisms of perception: achieving individual benefits such as enhanced Prediction, valuation, categorization (Coordinator: information access. The effects of taking part in Prof. Dr. Karl Gegenfurtner) social networks are under investigation. Subproject A3: Predictive perception: multisensory Funded by Zeppelin University Friedrichshafen consequences of one`s own actions Funding period until depletion of funding Principal investigator(s) T. Kircher, D. Leube & B. Straube Title Integrative analyses of genetic, epigenetic and Summary The investigations will focus on three environmental risk-factors of affective disorders different aspects of predictive mechanisms relevant
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Clinical Institutions
Principal investigator(s) A. Krug, M. Rietschel, S. Funded by DFG (FOR 2107, CP2) – German Research Witt & M. Nöthen Foundation, Research Unit Summary Within this FOR, a large sample of healthy Funding period 2014 – 2017 subjects and different patient groups is being investigated. This sub-project will perform genom- wide genotyping, methylation analyses etc. As the sample is being investigated at the moment within General information about the institute WP1, no analyses have been performed yet.
Funded by DFG (FOR 2107) – German Research Research funding 1.458.627,69 € Foundation, Research Unit Funding period 2014 – 2017
Title Methodological aspects of longitudinal imaging genetics MRI studies: reliability, quality assurance, Most important publications statistical genetics and genetic epidemiology Lueken U, Straube B, Konrad C, Wittchen HU, Principal investigator(s) A. Jansen, A. Dempfle Ströhle A, Wittmann A, Pfleiderer B, Uhlmann C, Summary Within this FOR, a large sample of healthy Arolt V, Jansen A, Deckert J, Kircher T (2013) Neural subjects and different patient groups is being Substrates of Treatment Response to Cognitive- investigated. This sub-project will perform genom- Behavioral Therapy in Panic Disorder With wide genotyping, methylation analyses etc. As the Agoraphobia. American Journal of Psychiatry sample is being investigated at the moment within 170:1345-1355 WP1, no analyses have been performed yet. Funded by DFG (FOR 2107) – German Research 1. Kircher T, Arolt V, Jansen A, Pyka M, Reinhardt I, Foundation, Research Unit Kellermann T, Konrad C, Lueken U, Gloster A, Funding period 2014 – 2017 Gerlach AL, Ströhle A, Wittmann A, Pfleiderer B, Wittchen HU, Straube B (2013) Effect of cognitive Title Dissecting the neurobiology in the course of behavioural therapy on the neural correlates of fear affective disorders – the Marburg affective disorders conditioning in panic disorder. Biological Psychiatry cohort study (MACS) 73:93-101 Principal investigator(s) U. Dannlowski, C. Konrad & 2. T. Kircher 3. Krug A, Krach S, Jansen A, Nieratschker V, Witt SH, Summary This Project constitutes the human Shah NJ, Nöthen MM, Rietschel M, Kircher T (2013) backbone study of the DFG-research group. N=2500 The effect of Neurogranin on neural correlates of human subjects (N=1000 patients suffering from episodic memory encoding and retrieval. affective disorders, N=1000 healthy subjects, N=500 Schizophrenia Bulletin 39:141-150 subjects at risk) will be recruited in a longitudinal 4. design and will undergo 1. Functional and structural 5. Straube B, Lueken U, Jansen A, Konrad C, Gloster magnetic resonance imaging, 2. Biomaterial AT, Gerlach AL, Ströhle A, Wittmann A, Pfleiderer B, assessment, 3. Deep clinical phenotyping. Follow-up Gauggel S, Wittchen HU, Arolt V, Kircher T (2014) sessions are scheduled 2 years after first Neural correlates of procedural variants in cognitive participation. behavioral therapy: A randomized, controlled Funded by DFG (FOR 2107, WP 1) – German multicentre fMRI study. Psychotherapy and Research Foundation, Research Unit Psychosomatics 83:222-233 Funding period 2014 – 2017 6. 7. Mehl S, Landsberg MW, Schmidt AC, Cabanis M, Title Management and Administration Bechdolf A, Herrlich J, Loos-Jankowiak S, Kircher T, Principal investigator(s) T. Kircher, K. Konrad & U. Kiszkenow S, Klingberg S, Kommescher M, Moritz S, Dannlowski Sartory G, Müller BW, Wiedemann G, Wittorf A, Summary Core project 2 (CP2) constitutes the Wölwer W, Wagner M (2014) Why do bad things administrative and coordinative core of the FOR happen to me? Attributional style, depressed mood, 2107. The main objectives are administration and and persecutory delusions in patients with coordination, organization of meetings and public schizophrenia. Schizophrenia Bulletin 40:1338-1346 relations. For example, CP2 organises administrative contacts, manages and assigns rotational positions 8. Straube B, Green A, Sass K, Kircher T (2014) Superior (GEROK), organizes meetings, conferences, and an temporal sulcus disconnectivity during processing of annual research retreat. Public visibility of the FOR metaphoric gestures in schizophrenia. Schizophrenia and transfer of research results will be granted by Bulletin 40:936-944 CP2. 9.
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Clinical Institutions
Opel N, Redlich R, Zwanzger P, Grotegerd D, Arolt V, Contact Details: Heindel W, Konrad C, Kugel H, Dannlowski U (2014) Rudolf-Bultmann-Str. 8, 35039 Marburg Hippocampal Atrophy in Major Depression-a Tel.:++49 (0) 6421-58 66219Director: Professor Dr. Function of Childhood Maltreatment Rather Than Tilo Kircher Diagnosis? Neuropsychopharmacology 39:2723-2731
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Department of Oral and Maxillofacial Surgery, Oral Surgery and Implantology
Chair Professor A. Neff subjective outcome parameters after surgical or conservative treatment. Professor C. Knabe-Ducheyne – Endowed Title Efficacy and mechanisms of biofeedback based Professorship of Experimental Orofacial behavioural therapy compared to dental splint Medicine therapy in the treatment of craniomandibular The Endowed Professorship of Experimental Orofacial disorders Medicine has an equal association with the Dept of Principal investigator(s) A. Neff, U. Lotzmann Prosthodontics and the Dept. of Maxillofacial Surgery. (Dental School) & U. Rief (Clinical Psychology) Dept. of Prosthodontics (U. Lotzmann) and Oral Summary This prospective randomized study deals and Maxillofacial Surgery (Professor A. Neff) with the interdisciplinary evaluation of specific therapy approaches in craniomandibular dysfunction (CMD) and evaluates the therapeutic standard Department of Oral and Maxillofacial Surgery options and their interdisciplinary combination. First results show profits for patients with muscle pain in a biofeedback setting. Main fields of research
Development and evaluation of innovative Title Laser-enhanced cytotoxicity of zoledronic acid osteosynthesis procedures (endoscopic assistance, and cisplatin on primary human fibroblasts and head condylar process and head fractures), TMJ disorders and neck squamous cell carcinoma cell line UM-SCC- and chronic pain, biphosphonate associated 3 osteonecrosis (BRONJ) and osteonecrosis after Principal investigator(s) Heymann PG, Mandic R, irradiation (ORN), speech improvement in cleft Kämmerer PW, Kretschmer F, Saydali A, Neff A, patients, bone microsection and bone Draenert FG histochemistry, mandibular tumor invasion Summary The purpose of this study was to investigate the combination of laser therapy with Research projects chemotherapy. Fibroblasts and tumour cells were Title pN1-study: efficacy of postoperative irradiation treated with zolendronic acid or cisplatin and in patients with squamous cell carcinomas of the irradiated with a laser. Cell viability was tested by mouth or oropharynx and simultaneously secured XTT. Irradiation alone increased bioviability, but solitary ipsilateral lymph node metastasis (pN1) - a under chemotherapy it lowered viability multi-centre clinical study significantly. In conclusion, radiation is able to raise Principal investigator(s) Mainz, Berlin, Hamburg, the cytotoxicity of chemotherapeutic drugs. Regensburg, Gießen, Marburg, Frankfurt, Tübingen, Funded by Research Foundation Dental e. V. Heidelberg, Rostock, Düsseldorf, Lübeck, Ulm, Wien Funding period 2013 – 2014 Summary Objective: assessment of the benefit of postoperative irradiation in patients with SCC. Title Development of a floor of the mouth squamous Patient selection: pT1 or pT2 tumours of the oral cell carcinoma rabbit animal model cavity and oropharynx with histological verification Principal investigator(s) R. Mandic, Dept. of ENT, C. of a singular ipsilateral lymph node metastasis (pN1) Knabe-Ducheyne, Dr. Bette, Dept. of Anatomy & Dr. and after R0-resecion, are divided into two groups P. Heymann, Dept. of Oral and Maxillofacial Surgery (irradiation vs wait and see), then the survival time is Summary This pilot study seeks to establish a floor measured. of the mouth squamous cell carcinoma rabbit animal model. Title Surgical versus conservative therapy in head fractures of the mandible - a multi-centre study Principal investigator(s) Berlin, Dresden, Innsbruck, Most important publications Leeds, Marburg, Oxford, Wien Hansen PJ, Knitschke M, Draenert FG, Irle S, Neff A Summary Objective: assessment of conservative (2013) Incidence of bisphosphonate-related versus surgical therapy options in condylar head osteonecrosis Clin Oral Investig 17(8):1829-37 fractures. Conservative treatment of head fractures is associated with a high rate of malfunction and Shedden Mora MC, Weber D, Neff A *, Rief W * adverse late sequelae. Surgical therapy has not been (2013) Biofeedback-based cognitive behavioral shown to be efficient in a randomized study yet. This treatment Clin J Pain 29(12):1057-65, *shared senior first multicenter study compares the functional and authorship
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Clinical Institutions
Makarova G, Bette M, Schmidt A, Jacob R, Cai C, Endowed Professorship of Experimental Rodepeter F, Betz T, Sitterberg J, Bakowsky U, Moll Orofacial Medicine – Professor C. Knabe- R, Neff A, Sesterhenn A, Teymoortash A, Ocker M, Ducheyne Werner JA, Mandic R (2013) Epidermal growth factor-induced modulation of cytokeratin expression Main fields of research levels influences the morphological phenotype of Regenerative medicine, bone regeneration, bioactive head and neck squamous cell carcinoma cells. Cell calcium phosphate bone grafting materials, bone- Tissue Res 351(1):59-72 tissue engineering utilizing resorbable calcium alkali
phosphate scaffolds produced by 3D printing, Neff A, Chossegros C, Blanc JL, Champsaur P, mesenchymal stem cell and microvascular Cheynet F, Devauchelle B, Eckelt U, Ferri J, Gabrielli techniques, moldable calcium alkali phosphate bone MF, Guyot L, Koppel DA, Meyer C, Müller B, grafting cements, individualized medicine, Peltomäki T, Spallaccia F, Varoquaux, , Wilk A, Pitak- antibacterial & bactericidal implant materials Arnnop P (2014) Position paper from the IBRA
Symposium on Surgery of the Head - The 2nd Research projects International Symposium for Condylar Fracture Title Rapidly resorbable calcium alkali Osteosynthesis, Marseille, France 12. J orthophosphate scaffolds for bone tissue Craniomaxillofac Surg 67:292-304 engineering.
Principal investigator(s) C. Knabe & Dr. G. Berger, Heymann PG, Mandic R, Kämmerer PW, Kretschmer Federal Institute for Materials Research and Testing, F, Saydali A, Neff A, Draenert FG (2014) Laser- Berlin enhanced cytotoxicity of zoledronic acid and Summary The objective of this project is to develop cisplatin on primary human fibroblasts and head and an adequate approach for regenerating large neck squamous cell carcinoma cell line UM-SCC-3. J segmental bone defects. To this end, three Craniomaxillofac Surg 42(7):1469-74 dimensional scaffolds with varying porosity are
fabricated from rapidly resorbable calcium alkali Wang S, Wang X, Draenert FG, Albert O, Schröder orthophoshates by 3 D printing or applying the HC, Mailänder V, Mitov G, Müller WE (2014) Schwarzwalder-Somers technique which utilizes Bioactive and biodegradable silica biomaterial for combustible polyurethane foam templates. In a first bone regeneration. Bone 67C:292-304 step the material and the printing process are Bhattacharyya S, Agrawal A, Knabe C, Ducheyne P optimized. Mesenchymal stem cells are then (2014) Sol-gel silica controlled release thin films for cultured on these scaffolds for two weeks under the inhibition of methicillin-resistant Staphylococcus perfusion. Subsequently the scaffolds are implanted aureus. Biomaterials 35(1):509-17 in segmental defects in the rat femur in conjunction
with a microvascular surgical technique in order to Stiller M, Kluk E, Bohner M, Lopez-Heredia MA, achieve adequate vascularization, which is of Müller-Mai C, Knabe C (2014) Performance of β- paramount importance when regenerating tricalcium phosphate granules and putty, bone segmental defects. grafting materials after bilateral sinus floor Funded by German Research Foundation-KN 377/8- augmentation in humans. Biomaterials 35(10):3154- 1, Federal Institute for Materials Research and 63 Testing
Funding period 2011 – 2015
Research funding 217,511.16 €*
*The funding obtained for instituting the Endowed Professorship of Experimental Orofacial Medicine has been raised by the Departments of Prosthodontics and Maxillofacial Surgery (50% each, i.e. 100,000 € annually).
Fig. 1 Tissue engineering approach and animal model using 3 D scaffolds and mesenchymal stem for regeneration of segmental defects in the rat femur
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Clinical Institutions
Title BioMimetic Bone - Biofunctionalized calcium phosphate scaffolds for fracture repair - Histologic evaluation. Principal investigator(s) C. Knabe-Ducheyne & PD Ch. Dr. Müller-Mai, Medical Faculty, University Bochum Summary This study evaluates the effect of tricalcium phosphate based scaffolds to whose surface bone morphogenetic proteins are adsorbed on bone regeneration of segmental defects after implantation in the rabbit ulna. Funded by Federal Ministry for Research and Technology Fig. 2 Animal model using 3 D scaffolds and mesenchymal stem Funding period 2012 – 2014 cells for regeneration of segmental defects in the rat femur in combination with a microvascular technique Title Effect of a silica containing calcium alkali Title The effect of hormone status on bone orthophosphate ceramic as compared to silicon regeneration after sinus floor augmentation with doped tricalcium phosphate on bone formation and porous tricalcium phosphate particles osteogenic marker expression after sinus floor Principal investigator(s) C. Knabe & PD. Dr. Dr. M. augmentation in humans." Stiller, Charité University Medical Center Berlin Principal investigator(s) C. Knabe & Dr. Stiller Summary This study elucidates the effect of age, Summary This study evaluates the effect of a silica BMI and gender related parameters such as containing calcium alkali orthophosphate ceramic as hormone status on bone regeneration after sinus compared to silicon doped tricalcium phosphate on floor augmentation with porous tricalcium bone formation and osteogenic marker expression phosphate particles in humans. after sinus floor augmentation in humans. Funded by Robert Mathys Foundation Funded by Zimmer Foundation Funding period 2008 – 2014 Funding period 2013 – 2014
Title BioMin II – Biofunctionalized calcium phosphate Title Effect of silk-based periodontal membranes on surfaces: adsorption mechanisms of bone guided bone regeneration morphogenetic proteins to the surfaces of calcium Principal investigator(s) C. Knabe phosphate bone grafting materials Summary This study evaluates the effect of a silk- Principal investigator(s) C. Knabe & PD Dr. Ch. based periodontal membranes on bone formation Müller-Mai, Medical Faculty, University Bochum and osteogenic marker expression after implantation Summary This study evaluates the effect of bone in an rabbit calvarial defect model. morphogenetic proteins, which are adsorbed onto Funded by Corporate Sponsor, BLS Preclinical the surface of bioactive glass 45S5 cylinders, on bone Services osteoblast differentiation and bone formation after Funding period 2011 – 2013 implantation in the rabbit femur. Funded by Federal Ministry for Research and Title Infected fractures – Treatment and Mitigation Technology of Biofilm Formation Funding period 2011 – 2014 Principal investigator(s) C. Knabe & Prof. Paul Ducheyne, Dept. of Bioengineering, University of Title Effect of various tricalcium calcium phosphate- Pennsylvania, Dr. J. Garino, Dept. of Orthopaedic based mesh and paste-like bone grafting materials Surgery, University of Pennsylvania on osteogenesis and bone regeneration after Summary This study evaluates the efficacy of implantation in critical-size defects in the sheep bactericidal sol-gel coatings on intramedullary scapula fracture fixation pins with controlled release of Principal investigator(s) C. Knabe vancomycin for preventing infection in a sheep Summary This study evaluates the effect of various model after inoculation with Staph. aureus. tricalcium calcium phosphate-based mesh and paste- Funded by US Department of Defense like bone grafting materials on osteoblast Funding period 2010 – 2013 differentiation and bone regeneration after implantation in critical-size defects in the sheep Title Preclinical Testing of Microparticle Ceramic scapula. Urethral Bulking Agents in a rat model Funded by Corporate Sponsor, Curasan Principal investigator(s) P. Zvara, Dept. of Surgery / Funding period 2013 – 2014 Urology, University of Vermont, C. Knabe-Ducheyne, Philipps University Marburg, A. El-Ghannam, Dept. of
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Clinical Institutions
Mechanical Engineering and Engineering Science, Most important publications The University of North Carolina at Charlotte Summary This study evaluates the efficacy of micro Stiller M, Kluk E, Bohner M, Lopez-Heredia MA, particle ceramic urethral bulking agents in a rat Müller-Mai C, Knabe C (2014) Performance of β- model tricalcium phosphate granules and putty, bone Funded by University of Vermont grafting materials after bilateral sinus floor Funding period 2014 – 2015 augmentation in humans. Biomaterials 35(10):3154- 63 Title Bone Tissue Engineering in Implant Dentistry Principal investigator(s) C. Knabe-Ducheyne Bhattacharyya S, Agrawal A, Knabe C, Ducheyne P Summary The objective of this project is to develop (2014) Sol-gel silica controlled release thin films for an adequate approach for regenerating large the inhibition of methicillin-resistant Staphylococcus aureus. Biomaterials 35(1):509-17 segmental bone defects. To this end, three dimensional scaffolds with varying porosity are Qu H, Knabe C, Burke M, Radin S, Garino J, Schaer T, fabricated from rapidly resorbable calcium alkali Ducheyne P (2014) Bactericidal micron-thin sol-gel orthophosphates by 3 D printing or applying the films prevent pin tract and periprosthetic infection. Schwarzwalder-Somers technique which utilizes Mil Med 179(8 Suppl):29-33 combustible polyurethane foam templates. In a first step the material and the printing process are Qu H*, Knabe C*, Radin S, Garino J, Ducheyne P. optimized. Mesenchymal stem cells are then Percutaneous external fixator pins with bactericidal cultured on these scaffolds for one to two weeks micron-thin sol-gel films for the prevention of pin under perfusion and the cellular response is tract infection. Biomaterials in press characterized. Subsequently the scaffolds are *authors have contributed equally implanted in segmental defects in the rat femur in Knabe C, Lopez Heredia MA, Barnemitz D, Genzel A, conjunction with a microvascular surgical technique Peters F, Hübner WD (2014) Effect of silicon-doped in order to achieve adequate vascularization, which calcium phosphate bone substitute materials on is of paramount importance when regenerating bone formation and osteoblastic phenotype segmental defects. expression in vivo. Key Engineering Materials Funded by DAAD – German Academic Exchange 614:31-14 Service Funding period 2014 Lopez-Heredia MA, Barnewitz D, Genzel A, Stiller M, Peters F, Huebner W-D, Stang B, Kuhr A, Knabe C Title Development of a floor of the mouth squamous (2014) In vivo osteogenesis assessment of a cell carcinoma rabbit animal model tricalcium phosphate paste and a tricalcium Principal investigator(s) R. Mandic, Dept. of ENT, C. phosphate foam bone grafting materials. Key Knabe-Ducheyne, Dr. Bette, Dept. of Anatomy & Dr. Engineering Materials 631:426-429 P. Heymann, Dept. of Oral and Maxillofacial Surgery Mann-Gow TK, Blaivas JG, King BJ, El-Ghannam A, Summary This pilot study seeks to establish a floor Knabe C, Lam MK, Kida M, Sikavi CS, Plante MK, of the mouth squamous cell carcinoma rabbit animal Krhut J, Zvara P. Rat animal model for preclinical model. testing of microparticle urethral bulking agents. Int J
Urol in press Title The effect of tricalcium phosphate ceramic particles and a tricalcium phosphate hyaluronic acid- based putty bone grafting material on bone regeneration after sinus floor augmentation using a split mouth design Research funding 260,872.73 € Principal investigator(s) C. Knabe & PD Dr. M. Stiller, Charité University Medical Center Berlin Contact Details: Summary This study elucidates the effect of Department of Oral and Maxillofacial Surgery, Oral tricalcium phosphate ceramic bone grafting particles Surgery and Implantology and a tricalcium phosphate hyaluronic acid-based Baldingerstr. , D-35043 Marburg putty bone grafting material on bone regeneration Phone:++49 (0) 6421-58 63239 and volume stability of the grafted area after sinus Director: Professor Andreas Neff floor augmentation in human using a split mouth design. Department of Experimental Orofacial Medicine; Funded by Robert Mathys Foundation c/o MZZMK, Georg-Voigt-Str. 4, D-35039 Marburg Funding period 2009 – 2013 Phone:++49 (0) 6421-58 61784 Prof. Christine Knabe-Ducheyne
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Clinical Institutions
Department of Orthodontics
Chair Professor H. M. Korbmacher-Steiner General information about the institute Main fields of research Relation of form and function Research funding 2.343,60 € Effects of RME (wanted and unwanted)
Enamel conditioning, sealing and bonding
New strategies of bracket bonding techniques Most important publications Impact of orthodontic therapy on cervical spine Laboratory evaluation of toothbrush/toothpaste posture abrasion resistance after smooth enamel surface 3D-Evaluation of CBCT including sealing (2013) Clin Oral Investig superimpositioning
Therapeutic effects of functional orthodontic Research Projects appliances on cervical spine posture: a retrospective Title Laboratory evaluation of toothbrush / cephalometric study (2014) Head Face Med toothpaste abrasion resistance after smooth enamel surface sealing Density of the midpalatal suture after RME Principal investigator(s) H. M. Korbmacher-Steiner, treatment - a retrospective comparative low-dose A. Hellak & M. Schauseil CT-study (2014) Head Face Med
Title Density of the midpalatal suture after RME treatment - a retrospective comparative low-dose CT-study Contact Details: Principal investigator(s) H. M. Korbmacher-Steiner, Georg-Voigt-Str. 3, 35039 Marburg A. Hellak & M. Schauseil Tel.:++49 (0) 6421-58 63218 Director: Professor Heike Korbmacher-Steiner Title Einfluss der chirurgisch unterstützten Hyrax- GNE und Hybrid-GNE auf die Weichteil-Morphologie der Nase – eine prospektive 3D RCT-Studie Principal investigator(s) H. M. Korbmacher-Steiner, A. Hellak & M. Schauseil
Title Influence of RME treatment on the postpubertal midpalatal suture – a comparative Low- Dose CT-study on sufficient retention time Principal investigator(s) H. M. Korbmacher-Steiner, A. Hellak & M. Schauseil
Title Einfluss unterschiedlicher Methoden des interproximalen Polishings auf das Demineralisa- tionsverhalten des Zahnschmelzes Principal investigator(s) H. M. Korbmacher-Steiner, A. Hellak & M. Schauseil
Title Einfluss der Hybrid-GNE versus der konventionellen GNE auf die Hart- und Weichteilveränderungen der Nase – eine retrospektive 3D Low-Dose-CT Studie an einem postpubertalen Patientenkollektiv Principal investigator(s) H. M. Korbmacher-Steiner, A. Hellak & M. Schauseil
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Department of Periodontology
Chair Professor N. Arweiler (Salviatop®) compared to another gel (Parodur®) and a chlorhexidine mouthrinse (Meridol®med CHX Main fields of research 0,2%) In the frame of infection biology and infection Principal investigator(s) N. Arweiler control, microbiology of the oral cavity and the Summary Aim of the blinded, randomized, four-cell, influence of systemic diseases on oral health are crossover study was the clinical evaluation of the examined clinically, radiologically and antibacterial effect of a new dental, antibacterial gel immunologically. Health services research deals with in comparison to another gel (Parodur®) and a the primary and secondary care as well as the chlorhexidine mouthrinse (Meridol®med CHX 0,2%) prevention of periodontal and perimplant disease solution. In a 4 day plaque regrowth study 24 especially aggressive forms. Especially new subjects refrained from all oral hygiene antibacterial agents and oral hygieare in vitro or measurements for the following 96 hours and clinically tested. applied instead one of the gels or rinsed with the chlorhexidine solution. Research projects Funded by Rottapharm, Madaus GmbH D-51101 Köln Title The effect of different cleaning modalities on Funding period 2014 – 2015 biofilm and inflammation in maintenance care of dental implants Principal investigator(s) N. Arweiler Title Antibacterial effect and substantivity of Summary Biofilm formation and inflammation is the toothpaste slurries in vivo main factor for peri-implant diseases and failures. Principal investigator(s) N. Arweiler Due to similarities to periodontitis, similar treatment Summary The aim of this blinded, randomized, four- principles are suggested. However their effect on cell, crossover study was to assess the antibacterial surface characteristics of implants has not yet effect and substantivity of toothpastes applied as investigated clinically. Possibly treatment can harm slurries on established dental biofilms over 24h. or roughen the surface of teeth or implants and Meridol® toothpaste was compared to a benchmark promotes biofilm formation. Recent findings – toothpaste and a positive and negative control after however on teeth - showed that after a single application on mature biofilm over an instrumentation with different curettes a rougher observation period of 24 hours. For this purpose, surface did not enhance microbial adhesion but lead twenty-four subjects were selected to participate in to an improved attachment of PDL fibroblasts. So the four test cycles. For each test cycle the subjects were aim of the study is to investigating three different requested to discontinue all oral hygiene measures treatment modalities and a control on clinical, for a period of 48 hours. The participants were then microbial and immunological parameter. required to rinse their mouth for one minute with Funded by Grant from Camlog Foundation one of the randomly allocated test or control Funding period 2012 – 2014 solutions. A plaque sample was taken from a defined pair of teeth every second hour up to 14 hours as Title In vitro-Study to evaluate the antibacterial well as 24 hours after application of the test pro- effect of Salviacur in comparison to a control duct. Vital staining of the sample was performed solution and chlorhexidine (0.2%) on an established each time to assess the vitality of the bacterial ex vivo plaque biofilm biofilm. Principal investigator(s) N. Arweiler Funded by GABA International AG, 4106 Therwil, Summary Aim of the in vitro study was the first Switzerland evaluation of an antibacterial effect of a new dental, Funding period 2014 antibacterial gel in comparison to a control/saline solution and chlorhexidine. Title In situ evaluation of the antibacterial effect of Funded by Rottapharm, Madaus GmbH D-51101 different restorative materials on in situ biofilm Köln formation: A controlled clinical study Funding period 2014 Principal investigator(s) T. M. Auschill & N. Arweiler Summary The purpose of the clinical study was to Title Double-blind, prospective, randomized, clinical investigate the influence of different composite cross-over study to evaluation the plaque reducing materials as well as glass-ionomer cements on the in and antibacterial effect of a new dental gel situ biofilm formation using an intraoral splint model
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Clinical Institutions and to compare it to enamel. Vitality of the biofilm Arweiler NB, Pietruska M, Pietruski J, Skurska A, as well as plaque coverage of the slabs was Dolińska E, Heumann C, Auschill TM, Sculean A examined after 72 biofilm development (2014) Six-month results following treatment of Funded by VOCO GmbH, Cuxhaven, Germany aggressive periodontitis with antimicrobial Funding period 2014 – 2015 photodynamic therapy or amoxicillin and metronidazole. Clin Oral Investig 18(9):2129-35 Title Effectivity and immunological mechanism of photodynamic therapy on oral lichen planus Netuschil L, Auschill TM, Sculean A, Arweiler NB Principal investigator(s) R. Cosgarea, N. Arweiler & (2014) Confusion over live/dead stainings for the M. Hertl detection of vital microorganisms in oral biofilms-- Summary Lichen planus (LP) is an inflammatory which stain is suitable? BMC Oral Health 14:2 disease, which shows characteristic clinical and histopathological features and involves skin and Arweiler NB, Netuschil L, Beier D, Grunert S, various mucous membrane. Although LP is known to Heumann C, Altenburger MJ, Sculean A, Nagy K, Al- be triggered by various factors, including drugs, Ahmad A, Auschill TM (2014) Action of food viruses and oral metals, pathogenic mechanisms is preservatives on 14-days dental biofilm formation, still unknown . Oral mucosal lesions of LP are called biofilm vitality and biofilm-derived enamel oral LP (OLP) and are characterized clinically by demineralisation in situ. Clin Oral Investig 18(3):829- erythemas and reticular lace-like whitish coating 38 with erosions and ulcers on the oral mucosa and lips, and histopathologically by massive infiltrates of Bassetti M, Schär D, Wicki B, Eick S, Ramseier CA, lymphocytes beneath basement membrane zone Arweiler NB, Sculean A, Salvi GE (2014) Anti- (BMZ). OLP is occasionally intractable to various infective therapy of peri-implantitis with adjunctive treatments, including topical steroids, topical local drug delivery or photodynamic therapy: 12- antifungals, various types of gurgle and oral health month outcomes of a randomized controlled clinical care, however none of these approaches can so far trial. Clin Oral Implants Res 25(3):279-87 resolve these inflammatory lesions. The photodynamic therapy (PDT) could be a treatment Polonyi M, Prenninger N, Arweiler NB, Haririan H, option but is relatively unknown. The study includes Winklehner P, Kierstein S (2013) Assessment of 24 patients suffering from OLP and receiving 5 viable periodontal pathogens by reverse treatment application of PDT. Both clinical and transcription quantitative polymerase chain immunohistologically parameter will be assessed reaction. J Periodontal Res 48(5):671-6 before and after PDT-treatment. Funded by UKGM – University Hospital Giessen and Döri F, Arweiler N, Húszár T, Gera I, Miron RJ, Marburg Sculean A (2013) Five-year results evaluating the Funding period 2014 effects of platelet-rich plasma on the healing of intrabony defects treated with enamel matrix derivative and natural bone mineral. J Periodontol 84(11):1546-55 General information about the institute
Contact Details: Research funding 188.463,46 € Georg-Voigt-Str. 3, 35033 Marburg Phone:++49 (0) 6421-58 63235 Director: Professor Nicole Arweiler Most important publications Auschill TM, Schmidt KE, Arweiler NB (2014) Resin Infiltration for Aesthetic Improvement of Mild to Moderate Fluorosis: A Six-month Follow-up Case Report. Oral Health Prev Dent 2014 Sep 18. doi: 10.3290/j.ohpd.a32785
Sculean A, Cosgarea R, Stähli A, Katsaros C, Arweiler NB, Brecx M, Deppe H (2014) The modified coronally advanced tunnel combined with an enamel matrix derivative and subepithelial connective tissue graft for the treatment of isolated mandibular Miller Class I and II gingival recessions: a report of 16 cases. Quintessence Int 45(10):829-35
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Clinical Institutions
Department of Operative Dentistry and Endodontics
Chair Professor Dr. R. Frankenberger Title Microparticulate silver for antimicrobial dental Professor Dr. A. Braun, Dr. M. J. Roggendorf applications Principal investigator(s) R .Frankenberger Main fields of research Summary Modification of resin-based adhesives, Operative Dentistry resin composites, and laquers with microparticulate a. Preclinical laboratory evaluation of dental silver additions for use in conservative dentistry in biomaterials for restorative techniques: Artificial order to prevent initial caries and to reduce mouth simulation of resin composite materials, glass recurrent caries. ionomer cements, postendodontic restoratives and Funded by EU – European Research Concil, EFRE techniques in order to predict their clinical behavior. Grant 1330/68562, Industry Analyses using scanning electron microscopy. Funding period 2009 – 2012, ongoing b. Randomized prospective clinical long-term trials Title Preclinical evaluation of adhesion, marginal as university based expert studies or practice based quality, crack formation and flexural fatigue behavior research investigations nationwide.c. Laser Dentistry Principal investigator(s) R. Frankenberger (caries diagnosis and treatment Fig. 1). Summary Intraoral simulation of different dental biomaterials in the artificial mouth using microtensile testing, thermomechanical loading, and wear determination, SEM margin analysis, handling properties, gap width, and dentists’ perception. Funded by Industry Funding period 2013 – 2014
Prospective clinical trials Clinical studies concerning resin-based biomaterials as both Dental School single and multi-center project as well as practice based research multi-center studies nationwide. Funded by Industry
Title Laser disinfection of root canals
Laser irradiation during antimicrobial photodynamic root canal Principal investigator(s) A. Braun & F. Schelle treatment (Fig.1) Summary The aim of the study was to evaluate different treatment protocols for root canal Endodontology disinfection. Root canals of extracted teeth were a. Strategies for optimization of endodontic prepared and inoculated with Enterococcus faecalis treatment, retreatment, and adhesive coronal seal. (E.f.). Root canals were cleaned using diode laser b. Evaluation of crack formation due to endodontic irradiation at different wavelengths and treatment. µ-CT evaluations of retreatment efficacy conventional rinsing with sodium hypochlorite. in endodontics (Fig. 2). Development of new root Colony forming units of E.f. were assessed before canal preparation and obturation instruments. and after treatment by a culturing procedure Funded by Sirona Dental Systems GmbH
Research projects Title Ultrasonical removal of subgingival calculus Title Development of low-shrink resin composites for Principal investigator(s) A. Braun & F. Schelle dental applications Summary Efficiency evaluation of a novel ultrasonic Principal investigator(s) R. Frankenberger system for calculus removal. Extracted human teeth Summary Innovative polymerization strategies for were treated in vitro using the ultrasonic device with resin composite restorations in conservative different power settings. Calculus removal was dentistry in order to reduce marginal gap formation assessed at constant intervals using an artificial and recurrent caries. periodontal pocket model. Residual calculus was Funded by BMWi ZIM/AiF FKZ KF2967801AK2 evaluated by means of digitized planimetry Funding period 2012 – 2014 Funded by Sirona Dental Systems GmbH
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Title Microhardness of cavity walls after (USPL) system. Lasers Med Sci [Epub ahead of print]. fluorescence aided caries excavation (FACE) DOI 10.1007/s10103-013-1344-z Principal investigator(s) A. Braun & R. Frankenberger Braun A, Beisel C, Brede O, Krause F (2013) Laser Summary The aim of the study was to compare the fluorescence of dentin caries covered with a novel microhardness of cavity walls after fluorescence nano-filled sealant. Lasers Med Sci 28:133-138 aided (FACE) and conventional caries removal. Extracted carious teeth were excavated with a bur. Bitter K, Gläser C, Neumann K, Blunck U, The endpoint of caries removal was determined Frankenberger R (2014) Analysis of resin-dentin either with a probe or using a fluorescence device. interface morphology and bond strength evaluation After treatment, teeth were cross sectioned through of core materials for one stage post-endodontic the prepared cavity and dentine microhardness was restorations. PLoS One 28:e86294 determined. Braun A, Kecsmar S, Krause, F, Berthold M, Frentzen Title Laser disinfection of periodontal tissues M, Frankenberger R, Schelle F (2014) Effect of Principal investigator(s) A. Braun & M. Krech simulated pulpal fluid circulation on intrapulpal Summary The aim of the study was to compare temperature following irradiation with an Nd:YVO4 different treatment protocols for disinfection of laser. Lasers Med Sci [Epub ahead of print]. DOI artificial periodontal lesions in vitro. Pig jaws were 10.1007/s10103-014-1540-5 used to prepare artificial periodontal pockets. After inoculation with a variety of periopathogenic Frankenberger R, Reinelt C, Krämer N (2014) microorganisms the lesions were cleaned using Nanohybrid vs. fine hybrid composite in extended diode laser irradiation at different wavelengths and class II cavities: 8-year results. Clin Oral Investig conventional rinsing. Bacterial counts were assessed 18:125-137 before and after treatment. Funded by Sirona Dental Systems GmbH Contact Details: Title Crack formation during postendodontic Georg-Voigt-Str. 3, 35039 Marburg treatment regimens Phone.:++49 (0) 6421-5863240 Principal investigator(s) M. J. Roggendorf Director: Professor Roland Frankenberger Summary Influence of different intracanal medications on tightness and bond strength of endodontic sealers Funded by Grant/Dental Chamber Hessen, Industry
General information about the institute
Research funding 327.714,91 €
Most important publications Frankenberger R, Hehn J, Hajtó J, Krämer N, Naumann M, Koch A, Roggendorf MJ (2013) Effect of proximal box elevation with resin composite on marginal quality of ceramic inlays in vitro. Clin Oral Investig 17:177-183
Pontius V, Pontius O, Braun A, Frankenberger R, Roggendorf MJ (2013) Retrospective evaluation of perforation repairs in 6 private practices. J Endod 39:1346-1358
Braun A, Krillke RF, Frentzen M, Bourauel C, Stark H, Schelle F (2013) Heat generation caused by ablation of dental hard tissues with an ultrashort pulse laser
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Clinical Institutions
Department of Pediatric and Community Dentistry
Chair Professor K. Pieper demineralized in a solution in order to simulate initial caries lesions. Main fields of research Funded by DGPZM-CP GABA Wissenschaftsfond Most of the multicenter studies carried out by the Funding period 2014 – 2015 Department of Pediatric Dentistry are focusing on the changes of oral health in children and Title Detection of interproximal carious lesions using adolescents over time. In retrospective and the NIR based camera VistaCam iX Proxi prospective studies we examine which measures Principal investigator (s) A.Jablonski-Momeni have contributed to the caries decline as a Summary Interproximal carious lesions are usually prerequisite for optimizing preventive programs. As detected by x-rays. Recently an X-ray-free method a foundation for these surveys several in-vitro and for proximal caries detection was introduced to the in-vivo studies have been performed dealing with market (VistaCam iX with the Proxi Head). The different diagnostic tools such as the International method is based on the near-infrared light
Caries Detection and Assessment System (ICDAS) for transillumination technology. The aim of this clinical the visual diagnosis of dental caries, laser devices, study is to evaluate the diagnostic accuracy of the fluorescence based cameras and impedance camera with respect to visual and radiographic spectroscopy. findings. Funded by Dürr Dental AG, Germany Research projects Funding period 2014 – 2015
Title Prevention in Primary Schools with Elmex Gelee® Principal investigator(s) K. Pieper Summary A preventive program utilizing Elmex General information about the institute Gelee® was introduced in primary schools consecutively to the Kindergarten program Research funding 34.413,51 € performed in Northern Hesse. The study carried concomitantly analyses the effect of this intensified preventive program. Additionally we are Most important publications investigating the question whether an intensified Pieper K, Weber K, Margraf-Stiksrud J, Heinzel- preventive programme in Kindergartens has a long Gutenbrunner M, Stein S, Jablonski-Momeni A lasting effect on oral health of school children. (2013) Evaluation of a preventive program aiming at Funded by GABA International children with increased caries risk using ICDAS II Funding period 2013 – 2015 criteria. Clin Oral Invest 17: 2049-2055
Title Effect of Curodont TM Protect on prevention of Jablonski-Momeni A, Liebegall F, Stoll R, Heinzel- artificial carious lesions of bovine enamel-an in-situ Gutenbrunner M, Pieper K (2013) Performance of a study new fluorescence camera for detection of occlusal Principal investigator A. Jablonski-Momeni caries in vitro. Lasers Med Sci 28: 101-109 Summary Initial carious lesions in enamel may progress towards dentine caries with decay without Pieper K, Lange J, Jablonski-Momeni A, Schulte AG any prevention. While an initial lesion can be (2013) Caries prevalence in 12-year-old children arrested with preventive measures, this is seldom from Germany: results f the 2009 national survey. the case in cavitations. The aim of this study is to Community Dent Health 30: 138-142 evaluate whether different measurements are able to arrest enamel lesions of further development. Stoll R, Urban-Klein B, Giacomin P, Loukas A, Two different methods serve as test group 1: the Jablonski-Momeni A (2013) In vivo assessment of established Duraphat varnish, 2: the newly caries excavation with a fluorescence camera developed Curodont Protect. The human saliva compared to direct bacteriolo-gical sampling and serves as control group without any intervention. For quantitative analysis using flow cytometry. Lasers each participant an individual removable resin Med Sci, DOI 10.1007/s10103-013-459-2 appliance is prepared. In each appliance demineralized bovine enamel specimens (sterilized, Jablonski-Momeni A, Winter J, Petrakakis P, BSE free) will be inserted. The specimen will be Schmidt-Schäfer S (2014) Caries prevalence (ICDAS)
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Clinical Institutions in 12-year-olds from low caries prevalence areas and association with independent variables. Int J Paediatric Dentistry 24: 90-97
Jablonski-Momeni A, Heinzel-Gutenbrunner M, Klein SMC (2014) In-vivo performance of the VistaProof fluorescence based camera for detection of occlusal lesions. Clinical Oral Invest 18, 1757-1762
Jablonski-Momeni A, Heinzel-Gutenbrunner M (2014) Efficacy of the “Self-assembling peptide P11- 4” in the formation of a remineralization scaffold on artificially induced enamel lesions on smooth surfaces. J Orofac Orthop 75, 175-189
Contact Details: Georg-Voigt-Str. 3, D-35033 Marburg Tel.:++49 (0) 6421-58 66690 Director: Professor Klaus Pieper
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Clinical Institutions
Department of Prosthodontics and Craniomandibular Function
Chair Professor U. Lotzmann Oral B and Philips using the experimental gingivitis Professor M. Gente, Professor R. Mengel model. Professor C. Knabe-Ducheyne – Endowed Funded by Philips Oral Health Care, USA Professorship of Experimental Orofacial Funding period 2010 – 2015 Medicine Title Vascular and nonvascular innervation of The Endowed Professorship of Experimenal Orofacial periodontal and periimplant tissue Medicine has an equal association with the Dept of Prinicipal investigator(s) R. Mengel & E. Weihe Prosthodontics and the Dept. of Maxillofacial Surgery. (Institute of Anatomy and Cell Biologie, Marburg) Summary Chemical coding of vascular and
nonvascular innervation in young and old human Main fields of research gingiva and periimplant soft tissue. 1. Risk factors affecting the success of dental Funded by GABA Lörrach implants and dental implant superstructures. Funding period 2008 – 2016 2. Histological, immunological and molecular biological characterization of the genesis of peri- Title Periodontitis as a risk factor for preterm birth implant diseases. Principal investigator(s) R. Mengel, M. Kühnert 3. Preventive measures and methods of treatment (Obstetrics and Perinatal Medicine, Marburg) for per-implant disease. Summary A long-term clinical study researching the 4. Influence of the intermaxillary relation and influence of periodontal disease on the prevalence stabilization on masticatory muscle activity and of preterm births. athletic performance. Funded by DGP/ARPA Foundation 5. Occlusal support and chewing efficiency Funding period 2009 – 2015 6. Application of eye-tracking in dentistry 7. Regenerative medicine, bone regeneration, Title Efficacy and mechanisms of biofeedback based bioactive calcium phosphate bone grafting behavioural therapy compared to dental splint materials, bone-tissue engineering utilizing therapy in the treatment of craniomandibular resorbable calcium alkali phosphate scaffolds disorders produced by 3D printing, mesenchymal stem cell Principal investigator(s) A. Neff & U. Lotzmann and microvascular techniques, moldable calcium (Dental School), U. Rief (Clinical Psychology), Philipps alkali phosphate bone grafting cements, University Marburg individualized medicine, antibacterial & Summary This prospective randomized study deals bactericidal implant materials. with the interdisciplinary evaluation of specific therapy approaches in craniomandibular dysfunction Research projects (CMD) and evaluates the therapeutic standard Title Establishment of a scientific database options and their interdisciplinary combination. First documenting data on patients with periodontal results show profits for patients with muscle pain in disease and dental implants a biofeedback setting. Principal investigator(s) R. Mengel & C. Schade- Brittinger (KKS Marburg) Title Influence of Implants und Locators for Summary The objective of this research project improved retention of mandibular full dentures on involves the documentation and scientific analysis of patient´s quality of life and oral function. A clinical, microbiological, radiological and controlled an prospective study immunological data from patients with periodontal Principal investigator(s) R. Mengel & U. Lotzmann disease and dental implants using a newly developed Summary In the controlled and prospective study scientific database. the influence of Implants and Locators for improved Funded by Nobel Biocare (Zürich, Switzerland) retention of mandibular full dentures on patient´s Funding period 2010 – 2016 oral function and quality of life will be examined. Funded by GC Europe (Leuven, Belgium) Title Comparison of 2 electric toothbrushers. An Funding period 2014 – 2016 experimental gingivitis trial Principal investigator(s) R. Mengel Summary The objective of this study is to directly examine and compare electric toothbrushes from
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Clinical Institutions
Most important publications Experimental Orofacial Medicine – Professor C. Thöne-Mühling M, Peleska B, Gockel F, Lotzmann U, Knabe-Ducheyne Mengel R (2013) Template-guided flapless implant insertion and prosthetic rehabilitation with Main fields of research telescopic crowns in a patient with treated Regenerative medicine, bone regeneration, bioactive generalized aggressive periodontitis: a case report. calcium phosphate bone grafting materials, bone- Quintessenz International 43:179-185 tissue engineering utilizing resorbable calcium alkali phosphate scaffolds produced by 3D printing, Swierkot K, Brusius M, Leismann D, Nonnenmacher mesenchymal stem cell and microvascular C, Nüsing R, Lubbe D, Schade-Brittinger C, Mengel R techniques, moldable calcium alkali phosphate bone (2013) Manual versus sonic-powered toothbrushing grafting cements, individualized medicine, for plaque reduction in patients with dental implants antibacterial & bactericidal implant materials – an explanatory randomized controlled trial. Eur J Oral Implantol 6(2): 133 – 144 Research projects Title Rapidly resorbable calcium alkali Lopez-Heredia MA, Pattipeilohy J, Hsu S, Grykien M, orthophosphate scaffolds for bone tissue van der Weijden B, Leeuwenburgh SCG, Wolke JGC engineering. and Jansen JA (2013) Bulk physicochemical, Principal investigator(s) C. Knabe & Dr. G. Berger, interconnectivity and mechanical properties of Federal Institute for Materials Research and Testing, calcium phosphate cements – fibrin glue composites Berlin for bone substitute applications. J Biomed Mater Res Summary The objective of this project is to develop A 101(2):478-90 an adequate approach for regenerating large segmental bone defects. To this end, three Eberle JC, Schneider J, Lotzmann U (2013) Initial dimensional scaffolds with varying porosity are effects of reduced vertical dimension on the fabricated from rapidly resorbable calcium alkali projection of body’s center of gravity on a standing orthophoshates by 3 D printing or applying the surface – a pilot study. J Craniomandib Function 5(2): Schwarzwalder-Somers technique which utilizes 151-161 combustible polyurethane foam templates. In a first step the material and the printing process are Shedden Mora MC, Weber D, Neff A, Rief W (2013) optimized. Mesenchymal stem cells are then Biofeedback-based cognitive-behavioral treatment cultured on these scaffolds for two weeks under Clin J Pain 29(12):1057-65 perfusion. Subsequently the scaffolds are implanted Bhattacharyya S, Agrawal A, Knabe C, Ducheyne P in segmental defects in the rat femur in conjunction (2014) Sol-gel silica controlled release thin films for with a microvascular surgical technique in order to the inhibition of methicillin-resistant Staphylococcus achieve adequate vascularization, which is of aureus. Biomaterials 35 (1):509-17 paramount importance when regenerating segmental defects. Stiller M, Kluk E, Bohner M, Lopez-Heredia MA, Funded by German Research Foundation-KN 377/8- Müller-Mai C, Knabe C. (2014) Performance of β- 1, Federal Institute for Materials Research and tricalcium phosphate granules and putty, bone Testing grafting materials after bilateral sinus floor Funding period 2011 – 2015 augmentation in humans. Biomaterials 35(10):3154- 63
Knabe C, Lopez Heredia MA, Barnemitz D, Genzel A, Peters F, Hübner WD (2014) Effect of silicon-doped calcium phosphate bone substitute materials on bone formation and osteoblastic phenotype expression in vivo. Key Engineering Materials 614:31-14
Research funding 215,304.43 €*
Fig. 1 Tissue engineering approach and animal model using 3 D *The funding obtained for instituting the Endowed scaffolds and mesenchymal stem for regeneration of segmental Professorship of Experimental Orofacial Medicine has been defects in the rat femur raised by the Departments of Prosthodontics and Maxillofacial Surgery (50% each, i.e. 100,000 € annually).
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Clinical Institutions
Title BioMimetic Bone - Biofunctionalized calcium phosphate scaffolds for fracture repair - Histologic evaluation. Principal investigator(s) C. Knabe-Ducheyne & PD Ch. Dr. Müller-Mai, Medical Faculty, University Bochum Summary This study evaluates the effect of tricalcium phosphate based scaffolds to whose surface bone morphogenetic proteins are adsorbed on bone regeneration of segmental defects after implantation in the rabbit ulna. Funded by Federal Ministry for Research and Technology Fig. 2 Animal model using 3 D scaffolds and mesenchymal stem cells for regeneration of segmental defects in the rat femur in Funding period 2012 – 2014 combination with a microvascular technique Title Effect of a silica containing calcium alkali Title The effect of hormone status on bone orthophosphate ceramic as compared to silicon regeneration after sinus floor augmentation with doped tricalcium phosphate on bone formation and porous tricalcium phosphate particles osteogenic marker expression after sinus floor Principal investigator(s) C. Knabe & PD. Dr. Dr. M. augmentation in humans." Stiller, Charité University Medical Center Berlin Principal investigator(s) C. Knabe & Dr. Stiller Summary This study elucidates the effect of age, Summary This study evaluates the effect of a silica BMI and gender related parameters such as containing calcium alkali orthophosphate ceramic as hormone status on bone regeneration after sinus compared to silicon doped tricalcium phosphate on floor augmentation with porous tricalcium bone formation and osteogenic marker expression phosphate particles in humans. after sinus floor augmentation in humans. Funded by Robert Mathys Foundation Funded by Zimmer Foundation Funding period 2008 – 2014 Funding period 2013 – 2014
Title BioMin II – Biofunctionalized calcium phosphate Title Effect of silk-based periodontal membranes on surfaces: adsorption mechanisms of bone guided bone regeneration morphogenetic proteins to the surfaces of calcium Principal investigator(s) C. Knabe phosphate bone grafting materials Summary This study evaluates the effect of a silk- Principal investigator(s) C. Knabe & PD Dr. Ch. based periodontal membranes on bone formation Müller-Mai, Medical Faculty, University Bochum and osteogenic marker expression after implantation Summary This study evaluates the effect of bone in an rabbit calvarial defect model. morphogenetic proteins, which are adsorbed onto Funded by Corporate Sponsor, BLS Preclinical the surface of bioactive glass 45S5 cylinders, on bone Services osteoblast differentiation and bone formation after Funding period 2011 – 2013 implantation in the rabbit femur. Funded by Federal Ministry for Research and Title Infected fractures – Treatment and Mitigation Technology of Biofilm Formation Funding period 2011 – 2014 Principal investigator(s) C. Knabe & Prof. Paul Ducheyne, Dept. of Bioengineering, University of Title Effect of various tricalcium calcium phosphate- Pennsylvania, Dr. J. Garino, Dept. of Orthopaedic based mesh and paste-like bone grafting materials Surgery, University of Pennsylvania on osteogenesis and bone regeneration after Summary This study evaluates the efficacy of implantation in critical-size defects in the sheep bactericidal sol-gel coatings on intramedullary scapula fracture fixation pins with controlled release of Principal investigator(s) C. Knabe vancomycin for preventing infection in a sheep Summary This study evaluates the effect of various model after inoculation with Staph. aureus. tricalcium calcium phosphate-based mesh and paste- Funded by US Department of Defense like bone grafting materials on osteoblast Funding period 2010 – 2013 differentiation and bone regeneration after implantation in critical-size defects in the sheep Title Preclinical Testing of Microparticle Ceramic scapula. Urethral Bulking Agents in a rat model Funded by Corporate Sponsor, Curasan Principal investigator(s) P. Zvara, Dept. of Surgery / Funding period 2013 – 2014 Urology, University of Vermont, C. Knabe-Ducheyne, Philipps University Marburg, A. El-Ghannam, Dept. of
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Mechanical Engineering and Engineering Science, Most important publications The University of North Carolina at Charlotte Summary This study evaluates the efficacy of micro Stiller M, Kluk E, Bohner M, Lopez-Heredia MA, particle ceramic urethral bulking agents in a rat Müller-Mai C, Knabe C (2014) Performance of β- model tricalcium phosphate granules and putty, bone Funded by University of Vermont grafting materials after bilateral sinus floor Funding period 2014 – 2015 augmentation in humans. Biomaterials 35(10):3154- 63 Title Bone Tissue Engineering in Implant Dentistry Principal investigator(s) C. Knabe-Ducheyne Bhattacharyya S, Agrawal A, Knabe C, Ducheyne P Summary The objective of this project is to develop (2014) Sol-gel silica controlled release thin films for an adequate approach for regenerating large the inhibition of methicillin-resistant Staphylococcus aureus. Biomaterials 35(1):509-17 segmental bone defects. To this end, three dimensional scaffolds with varying porosity are Qu H, Knabe C, Burke M, Radin S, Garino J, Schaer T, fabricated from rapidly resorbable calcium alkali Ducheyne P (2014) Bactericidal micron-thin sol-gel orthophosphates by 3 D printing or applying the films prevent pin tract and periprosthetic infection. Schwarzwalder-Somers technique which utilizes Mil Med 179(8 Suppl):29-33 combustible polyurethane foam templates. In a first step the material and the printing process are Qu H*, Knabe C*, Radin S, Garino J, Ducheyne P. optimized. Mesenchymal stem cells are then Percutaneous external fixator pins with bactericidal cultured on these scaffolds for one to two weeks micron-thin sol-gel films for the prevention of pin under perfusion and the cellular response is tract infection. Biomaterials in press characterized. Subsequently the scaffolds are *authors have contributed equally implanted in segmental defects in the rat femur in Knabe C, Lopez Heredia MA, Barnemitz D, Genzel A, conjunction with a microvascular surgical technique Peters F, Hübner WD (2014) Effect of silicon-doped in order to achieve adequate vascularization, which calcium phosphate bone substitute materials on is of paramount importance when regenerating bone formation and osteoblastic phenotype segmental defects. expression in vivo. Key Engineering Materials Funded by DAAD – German Academic Exchange 614:31-14 Service Funding period 2014 Lopez-Heredia MA, Barnewitz D, Genzel A, Stiller M, Peters F, Huebner W-D, Stang B, Kuhr A, Knabe C Title Development of a floor of the mouth squamous (2014) In vivo osteogenesis assessment of a cell carcinoma rabbit animal model tricalcium phosphate paste and a tricalcium Principal investigator(s) R. Mandic, Dept. of ENT, C. phosphate foam bone grafting materials. Key Knabe-Ducheyne, Dr. Bette, Dept. of Anatomy & Dr. Engineering Materials 631:426-429 P. Heymann, Dept. of Oral and Maxillofacial Surgery Mann-Gow TK, Blaivas JG, King BJ, El-Ghannam A, Summary This pilot study seeks to establish a floor Knabe C, Lam MK, Kida M, Sikavi CS, Plante MK, of the mouth squamous cell carcinoma rabbit animal Krhut J, Zvara P. Rat animal model for preclinical model. testing of microparticle urethral bulking agents. Int J
Urol in press Title The effect of tricalcium phosphate ceramic particles and a tricalcium phosphate hyaluronic acid- based putty bone grafting material on bone regeneration after sinus floor augmentation using a split mouth design Research funding 260,872.73 € Principal investigator(s) C. Knabe & PD Dr. M. Stiller, Charité University Medical Center Berlin Summary This study elucidates the effect of Contact Details: tricalcium phosphate ceramic bone grafting particles Georg-Voigt-Str. 8, 35039 Marburg and a tricalcium phosphate hyaluronic acid-based Phone:++49 (0) 6421-58 66423 putty bone grafting material on bone regeneration Director: Professor Ulrich Lotzmann and volume stability of the grafted area after sinus floor augmentation in human using a split mouth design. Experimental Orofacial Medicine; Funded by Robert Mathys Foundation c/o MZZMK, Georg-Voigt-Str. 4, D-35039 Marburg Funding period 2009 – 2013 Phone:++49 (0) 6421-58 61784 Prof. Christine Knabe-Ducheyne
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Coordination Centre for Clinical Trials
Chair C. Schade-Brittinger Title VENUS-2 Principal investigator(s) Prof. Wolf Main fields of research Summary An open label phase I dose escalation of The KKS Marburg with its 30 staff members oral BIBF 1120 in combination with intravenous (www.kks.uni-marburg.de) is member of the KKS- carboplatin and vinorelbine in elderly patients with Network, a consortium of currently 19 German advanced Non-Small Lung Cancer - Stage VI clinical trial units at university hospitals. All Funded by Aktion Bronchialkarzinom (ABC) e.V requirements according to GCP are well established Funding period 2012 – 2013 including administration as well as central randomization, data management, statistics, quality Title GYN-7 management and monitoring. KKS Marburg is the Principal investigator(s) P. Harter legal representative of the University for investigator Summary Phase II-Studie zum Einsatz der initiated trials and the global contract management Kombinationschemotherapie PegLiposomales office of the University for all patient-related trials. Doxorubicin (PLD) und Carboplatin bei Currently, KKS is in charge of more than 30 running gynäkologischen Sarkomen und gemischt epithelial- multi-center clinical trials and also engaged in mesenchymalen Tumoren. training related to scientific and organizational Funded by AGO Study Group aspects of trials. Funding period 2008 – 2014
Research projects Title Ovar 16 Title Promid Principal investigator(s) A. du Bois Principal investigator(s) R. Arnold Summary A Phase III Study to evaluate the efficacy Summary Untersuchung des Gesamtüberlebens von and safety of Pazopanib monotherapy versus Patienten, die an der PROMID-Studie teilgenommen placebo in women who have not progressed after haben, nachdem Sandostatin® abgesetzt wurde first line chemotherapy for Epithelial Ovarian, Funded by Industry Fallopian Tube, or Primary Peritoneal. Funding period 2001 – 2013 Funded by AGO Study Group Funding period 2010 – 2014 Title MAGIKA Principal investigator(s) B. Maisch Title Desktop III Summary Umsetzung des Behandlungspfades zur Principal investigator(s) P. Harter Diagnostik und Therapie der DCM mit und ohne Summary Eine randomisierte, multizentrische Studie Inflammation in der integrierten Struktur eines zum Vergleich der Wirksamkeit einer zusätzlichen Klinikkonzerns (Rhön AG) unter Berücksichtigung Tumordebulking-Operation gegen eine alleinige eines universitären Zentrums Chemotherapie bei Patientinnen mit einem platin- Funded by Industry sensiblem Ovarialkarzinom-rezidiv. Funding period 2009 – 2013 Funded by AGO Study group Funding period 2010 – 2015 Title SELECT A Principal investigator(s) Prof. Wolf Title ATIP Summary TS stratified Chemotherapy and VEGF Principal investigator(s) T. Gress Inhibition in Non-Squamous Non-Small Cell Lung Summary Multicentre Phase II-trial to investigate Cancer - Stage IV the safety and the effects of ERBITUX® and Funded by Aktion Bronchialkarzinom (ABC) e.V. Gemcitabine in Patients with R0 resected Funding period 2012 – 2013 Adenocarcinoma of the pancreas. Funded by Industry Title VENUS-1 Funding period 2005 – 2013 Principal investigator(s) Prof. Wolf Summary An open label phase I dose escalation of Title BIOPACE oral BIBF 1120 in combination with intravenous Principal investigator(s) R. Funck vinorelbine in elderly patients with advanced Non- Summary Biventricular Pacing for Atrioventricular Small Lung Cancer - Stage VI Block in Left Ventricular Dysfunction to Prevent Funded by Aktion Bronchialkarzinom (ABC) e.V Cardiac Desynchronization Funding period 2012 – 2013 Funded by Industry
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Clinical Institutions
Funding period 2001 – 2015 advanced and/or metastatic liposarcoma who have relapsed following standard therapies or for whom Title Sormain no standard therapy exists. Principal investigator(s) A. Burchert Funded by Onkologisches Liposarkom-Netz,Spanien Summary Eine doppelblinde, Placebo-kontrollierte, Funding period 2012 – 2015 randomisierte, multizentrische Phase II Studie zur Untersuchung der Wirksamkeit und Sicherheit einer Title Earlystim-PSFU Sorafenib Erhaltungstherapie bei Patienten mit Flt3- Principal investigator(s) G. Deuschl ITD positiver AML in kompletter hämatologischer Summary Post Study follow-up to the study: The Remission (CHR) nach allogener Stammzell- effect of deep brain stimulation of the Subthalamic transplantation (allo-SCT). Nucleus (STN-DBS) on quality of life in comparosin to Funded by Industry best medical treatment in patients with complicated Funding period 2009 – 2015 Parkinson´s desease and preserved psychosocial competence (EarlyStim). Title OVAR 12 Funded by Industry Principal investigator(s) A. du Bois Funding period 2007 – 2018 Summary Multicenter, randomised, double-blind Phase III trial to investigate the efficacy and safety of Title EDNET BIBF 1120 in combination with carboplatin and Principal investigator(s): B. Herpertz-Dahlmann paclitaxel compared to placebo plus carboplatin and (ANDI), Prof. Zipfel; Prof. Herzog (ANTOP), C. Jacobi paclitaxel in patients with advanced ovarian cancer. (INA), M. de Zwaan (Interbed) Funded by AGO Study group Summary Zentrale biostatistische Betreuung, Daten- Funding period 2012 – 2015 und Datenqualitätsmanagement für den Forschungsverbund zur Psychotherapie bei Title OVAR 17 Essstörungen, gemeinsam mit dem Institut für Med. Principal investigator(s) J. Pfisterer Biometrie und Epidemiologie (Eating Disorders Summary A prospective randomised Phase III trial to Diagnostic Treatment Network, EDNET) evaluate optimal treatment duration of first-line Funded by BMBF – Federal Ministry of Education bevacizumab in combination with carboplatin and and Research paclitaxel in patients with primary epithelial ovarian, Funding period 2006 – 2013 fallopian tube or peritoneal cancer. The BOOST (Bevacizumab Ovarian Optimal Standard Treatment) Title Ovar 2.16 (Mito-8) Trial. Principal investigator(s) K. Baumann Funded by AGO Study group Summary Stealth Liposomal Doxorubicin vs Funding period 2011 – 2016 Carboplatin/Paclitaxel in Patients With Ovarian Cancer Recurrence Between Six and Twelve Months Title GYN-8 After Previous Platinum Based Chemotherapy: Phase Principal investigator(s) G. Emons III Multicenter Randomized Study (MITO-8; AGO- Summary Wirksamkeit, Verträglichkeit und OVAR). Sicherheit von Temsirolimus beim platinrefraktären Funded by BMBF - Federal Ministry of Education and Ovarialkarzinom und beim fortgeschrittenen oder Research rezidivierten Endometriumkarzinom. Funding period 2010 – 2014 Funded by AGO Study group Funding period 2011 – 2015 Title LION Principal investigator(s) U. Wagner Title OVAR 2.15 Aurelia Summary An open randomized prospective Principal investigator(s) F. Hilpert multicenter-trial “Lymphadenectomy in ovarian Summary A multi-centre, open-label, randomised, neoplasms (LION)” two-arm Phase III trial of bevacizumab plus Funded by DFG – German Science Foundation chemotherapy versus chemotherapy alone in Funding period 2008 – 2017 patients with platinum-resistant, epithelial ovarian, fallopian tube or primary peritoneal cancer. Title IA-Pem Funded by AGO Study group Principal investigator(s) R. Eming & E. Schmidt Funding period 2013 Summary Efficacy and safety of adjuvant immuno- adsorption in pemphigus vulgaris and pemphigus Title GEIS-Liposarcom foliaceus (IA-pem-study). Principal investigator(s) C. Valverde Morales Funded by DFG – German Research Foundation Summary Phase II Clinical Trial of Pazopanib to Funding period 2010 – 2015 evaluate the activity and tolerability in patients with
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Title UGMLC resistant epithelial ovarian cancer and low HER3 Summary Clinical Trial unit for the UGMLC – Module mRNA expression. Lung Funded by AGO Study group Funded by State Hessen – LOEWE Centre Funding period 2013 – 2016 Funding period 2010 – 2015 Title LDE225 Title BILANZ Principal investigator(s) T. Gress Principal investigator(s) Prof. Dr. Pfeilschifter Summary Phase I Trial with Post-Study Follow-up to Summary Randomisierte, partiell doppelblinde, Evaluate the Safety and Tolerability of LDE225 and placebokontrollierte, multizentrische Studie zur Octreotide LAR in Patients with Progressive Evaluation der Wirksamkeit und Sicherheit von Neuroendocrine Tumors. Bisphosphonaten in der Langzeittherapie der Funded by Industry Osteoporose (BILANZ). Funding period 2013 – 2016 Funded by BMBF Funding period 2012 – 2013 Title AGO-TR 1 Principal investigator(s) P. Harter Title NIC-PD Summary BRCA-Screening in Ovarian Cancer Principal investigator(s) W. Oertel (Protocol ID: AGOTR-1). Incidence of BRCA in tumor Summary A randomized, placebo-controlled, double- samples in Ovarian Cancer. blind, multi-centre trial to assess the disease- Funded by: AGO Study group modifying potential of transdermal nicotine in early Funding period: 2014-2019 Parkinson's disease in Germany and the USA Funded by Michael J. Fox Foundation Title CORSETT Funding period 2009 – 2017 Principal investigator(s) P. Harter Summary CORSETT - Current Ovarian geRm cell and Title FirstMapp SEx cord Tumor Treatment strategies - An Principal investigator(s) M. Fassnacht observational retrospective study of treatment Summary First International Randomized Study strategies for ovarian germ cell and sex cord-stromal placebo in MAlignant Progressive tumors in Germany. Pheochromocytoma and Paraganglioma (PPGL) Funded by Uniklinikum Freiburg Funding period 2014 – 2016 Funded by BMBF – Federal Ministry of Education and Research Title Alphasom Funding period 2013 – 2020 Principal investigator(s) W. Rief
Summary Alternative dosing regimens in the Title PATENT pharmacotherapy of mild to moderate insomnia Principal investigator(s) L. Eberhart Funded by DFG – German Research Foundation Summary Funding period 2013 – 2014 Funded by Industry
Funding period 2013 – 2015 Title CORRA
Principal investigator(s) J. Braun Title OVAR 2.21 Summary Comparison of the efficacy and safety of Principal investigator(s) K. Baumann two starting dosages of prednisolone in early active Summary A prospective randomized Phase III trial of rheumatoid arthritis: a randomized, placebo carboplatin/gemcitabine/bevacizumab vs. controlled trial carboplatin/pegylated liposomal Funded by BMBF – Federal Ministry of Education doxorubicin/bevacizumab in patients with platinum- and Research über Universität Bochum sensitive recurrent ovarian cancer. Funding period 2013 – 2016 Funded by AGO Study Group
Funding period 2013 – 2019 Title INTRANS
Principal investigator(s) D. K. Bartsch Title OVAR 2.20 Summary Fortlaufende Intrakutannaht oder Principal investigator(s) C. Kurzeder transkutaner Klammernahtverschluss bei elektiven Summary A two-part, randomized phase II, double- abdominal chirurgischen Eingriffen - Eine blind, multicenter trial assessing the efficacy and prospektive, randomisierte, kontrollierte, safety of Pertuzumab in combination with standard monozentrische, klinische Studie zur Evaluierung des chemotherapy vs. placebo plus standard postoperativen oberflächlichen Wundinfekts. chemotherapy in women with recurrent platinum Funded by UKGM – University Hospital Giessen and Marburg
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Funding period 2013 – 2015 Most important publications Fensterer H, Schade-Brittinger C, Muller HH, Tebbe Title ADIUVO Ens@t-Cancer S, Fass J, Lindig U, Settmacher U, Schmidt WE, Principal investigator(s) M. Fassnacht Marten A, Ebert MP, Kornmann M, Hofheinz R, Summary Efficacy of adjuvant mitotane treatment in Endlicher E, Brendel C, Barth PJ, Bartsch DK, Michl P, prolonging recurrence-free survival in patients with Gress TM (2013) Multicenter phase II trial to adrenocortical carcinoma at low-intermediate risk of investigate safety and efficacy of gemcitabine recurrence. combined with cetuximab as adjuvant therapy in Funded by EU – European Union pancreatic cancer (ATIP). Ann Oncol 24(10):2576-81 Funding period 2010 – 2015 Schuepbach WMM*, Rau J*, Knudsen K*, Volkmann Title ENCERT J, Krack P, Timmermann L, Hälbig TD, Hesekamp H, Principal investigator(s) Prof. Dr. med. Winfried Rief Navarro SM, Meier N, Falk D, Mehdorn M, Paschen Summary Enriching Cognitive-behavioral Therapy S, Maarouf M, Barbe MT, Fink GR, Kupsch A, Gruber (CBT) with Emotion Regulation Training (ERT) in D, Schneider G-H, Seigneuret E, Kistner A, Chaynes P, Patients with Multiple Somatoform Symptoms: Ory-Magne F, Brefel Courbon C, Vesper J, Schnitzler ENCERT A, Wojtecki L, Houeto J-L, Bataille B, Maltête, D, Funded by DFG Damier P, Raoul S, Sixel-Doering F, Hellwig D, Funding period 2013 – 2016 Gharabaghi A, Krüger R, Pinsker MO, Amtage F, Régis J-M, Witjas T, Thobois S, Mertens P, Kloss M, Title COPD SB010 Hartmann A, Oertel WH, Post B, Speelman H, Agid Principal investigator(s) C. Vogelmeier Y*, Schade-Brittinger C*, Deuschl G* (2013) Summary Clinical study to investigate safety, Neurostimulation for Parkinson's Disease with Early tolerability, efficacy, pharmacokinetics and Motor Complications. New England Journal of pharmacodynamics of inhaled multiple doses of the Medicine 368(7): 610-622; *shared authorship human GATA-3-specific DNAzyme solution SB010 in patients with moderate to severe COPD – A Zipfel S, Wild B, Groß G, Friederich H-C, Teufel M, randomised, double-blind, parallel group, Schellberg D, Giel KE, De Zwaan M, Dinkel A, multicenter, phase IIa pilot study. Herpertz S, Burgmer M, Löwe B, Tagay S, Von Funded by BMBF – Federal Ministry of Education Wietersheim J, Zeeck A, Schade-Brittinger C, and research, Helmholtz und Industry Schauenburg H, Herzog W (2014) Focal Funding period 2013 – 2015 psychodynamic therapy, cognitive behaviour therapy, and optimised treatment as usual in Title HD-DBS Huntington II outpatients with anorexia nervosa (ANTOP study): Principal investigator(s) J. Vesper randomised controlled trial. Lancet 383(9912):127- Summary Deep Brain Stimulation (DBS) of the 37 Globus pallidus (GP) in Huntington’s disease (HD): A prospective, randomised, controlled, international, Du Bois A, Floquet A, Kim JW, Rau J, Del Campo JM, multi-centre study Friedlander M, Pignata S, Fujiwara K, Vergote I, Funded by DFG – German Research Foundation, Colombo N, Mirza MR, Monk BJ, Kimmig R, Ray- über Universität Düsseldorf Coquard I, Zang R, Diaz-Padilla I, Baumann KH, Funding period 2014 – 2016 Mouret-Reynier MA, Kim JH, Kurzeder C, Lesoin A, Vasey P, Marth C, Canzler U, Scambia G, Shimada M, Title ClaSP Calvert P, Pujade-Lauraine E, Kim BG, Herzog TJ, Principal investigator(s) R. Dodel Mitrica I, Schade-Brittinger C, Wang Q, Crescenzo R, Summary JPND Verbundprojekt CLaSP, Versorgung Harter P (2014) Incorporation of Pazopanib in von Patienten im fortgeschrittenen Stadium der Maintenance Therapy of Ovarian Cancer. J Clin Oncol Parkinson-Krankheit, TP 32(30):3374-82 Funded by BMBF – Federal Ministry of Education and Research Herpertz-Dahlmann B, Schwarte R, Krei M, Egberts K, Funding period 2014 – 2017 Warnke A, Wewetzer C, Pfeiffer E, Fleischhaker C, Scherag A, Holtkamp K, Hagenah U, Buhren K, Konrad K, Schmidt U, Schade-Brittinger C, Timmesfeld N, Dempfle A (2014) Day-patient treatment after short inpatient care versus General information about the institute continued inpatient treatment in adolescents with anorexia nervosa (ANDI): a multicentre, randomised, Research funding 1.826.640,37 € open-label, non-inferiority trial. Lancet 383(9924): 1222-9
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Schüpbach W.M.M., Rau J, Houeto J-L, Krack P, Schnitzler A, Schade-Brittinger C, Timmermann L, Deuschl G (2014) Myths and facts about the EARLYSTIM study. Mov Disord 29(14):1742-50
Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, Sorio R, Vergote I, Witteveen P, Bamias A, Pereira D, Wimberger P, Oaknin A, Mirza MR, Follana P, Bollag D, Ray- Coquard I (2014) Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 32(13):1302-8
Trillsch F, Mahner S, Woelber L, Vettorazzi E, Reuss A, Ewald-Riegler N, de Gregorio N, Fotopoulou C, Schmalfeldt B, Burges A, Hilpert F, Fehm T, Meier W, Hillemanns P, Hanker L, Hasenburg A, Strauss HG, Hellriegel M, Wimberger P, Baumann K, Keyver-Paik MD, Canzler U, Wollschlaeger K, Forner D, Pfisterer J, Schroeder W, Muenstedt K, Richter B, Kommoss F, Hauptmann S, du Bois A (2014) Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study. Ann Oncol 25(7):1320-7
Contact Details: Karl-von-Frisch-Str. 4, 35043 Marburg Tel.:++49 (0) 6421-28 66458 Director: Carmen Schade-Brittinger
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